On December 5, 2015 Incyte Corporation (Nasdaq:INCY) reported data from two Phase 3 studies evaluating the long-term safety and efficacy of Jakafi (ruxolitinib) in patients with Myeloproliferative Neoplasms (MPNs) (Press release, Incyte, DEC 5, 2015, View Source;p=RssLanding&cat=news&id=2120390 [SID:1234508420]). In myelofibrosis (MF), results of a five-year follow-up from the COMFORT-II study demonstrate a continued survival benefit in patients originally randomized to ruxolitinib compared with patients randomized to best available therapy (BAT), with a 33 percent reduction in the risk of death (HR, 0.67; 95%CI, 0.44-1.02; P=.06). Because patients in the BAT arm had crossed over to receive ruxolitinib therapy (median 17 months after randomization), these data may suggest that earlier treatment with ruxolitinib may be associated with improved long-term survival in patients with intermediate-2 or high-risk MF. Additionally, 53 percent of patients treated with ruxolitinib (n=78/146) achieved at least a 35 percent reduction in spleen volume from baseline that was sustained over time (median duration 3.2 years).

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"These data from the COMFORT-II study reinforce the positive and long-term clinical benefits seen in patients with myelofibrosis who are treated with Jakafi," said Rich Levy, MD, Chief Drug Development Officer, Incyte. "The reduction in the risk of death and the sustained improvements in spleen volume are meaningful and important results for the community of patients with this rare blood cancer."

An analysis of the RESPONSE study is also planned for presentation at ASH (Free ASH Whitepaper). Previously published results in the New England Journal of Medicine showed that treatment with ruxolitinib, compared to standard therapy improved hematocrit control and reduced spleen volume in patients with polycythemia vera (PV) who had an inadequate response to or had unacceptable side effects from hydroxyurea (HU). The data at ASH (Free ASH Whitepaper) demonstrate that in patients with elevated white blood cell (WBC) counts at baseline, a greater proportion of patients in the ruxolitinib treatment arm (45%) achieved normalization of their WBC counts (achieving a WBC ≤10×109/L or a ≥50% reduction from baseline) compared to BAT (22%) or HU (9%) at week 32.
These data are scheduled for presentation at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting taking place December 5-8, 2015 in Orlando, FL.

Results from the COMFORT-II Study

Data from a five-year follow-up of the COMFORT-II trial, a randomized, open-label Phase 3 study evaluating long-term safety and efficacy of ruxolitinib in patients with intermediate-2 or high-risk primary myelofibrosis, post-PV myelofibrosis, or post-ET myelofibrosis, allowing crossover from the BAT arm to ruxolitinib after 48 weeks upon protocol-defined progression, revealed that 53 percent of patients treated with ruxolitinib (n=78/146) achieved at least a 35 percent reduction in spleen volume from baseline while on treatment during the study. Additionally, approximately one-third of evaluable JAK2 V617F-positive patients had more than a 20 percent reduction in allele burden at 3.2 years (38%) and 3.7 years (31%). Patients treated with ruxolitinib also experienced improvements in bone marrow fibrosis (15.8%) with 32.2 percent reporting stable fibrosis scores.

Overall, 59 (40%) and 35 (48%) deaths were reported in the ruxolitinib and BAT arms, respectively. Median overall survival (OS) was not reached in the ruxolitinib arm and was 4.1 years in the group of patients originally receiving BAT. There was a 33 percent reduction in risk of death with ruxolitinib (HR, 0.67; 95 percent CI, 0.44-1.02; P=.06). The estimated probability of survival at 5 years was 56 percent with ruxolitinib and 44 percent with patients originally receiving BAT. At week 48, BAT patients were allowed to cross over to receive ruxolitinib upon protocol-defined progression and after week 48 all BAT patients, irrespective of their progression status, were allowed to crossover to receive ruxolitinib; therefore, a confounding effect on OS was observed. An analysis correcting for crossover will be presented.

Adverse events (AEs) were consistent with those reported in previous studies of ruxolitinib and there was no increase in the incidence of AEs with longer exposure to treatment.

COMFORT-II is scheduled for presentation as an oral session by Dr. Claire Harrison, Guy’s and St. Thomas’ NHS Foundation Trust, Guy’s Hospital, Saturday, December 5, 2015, 9:30-11:30 AM EST, Room W224.

Results from the RESPONSE Study
The RESPONSE trial is a Phase 3 open-label study evaluating long-term safety and efficacy of ruxolitinib in patients with PV compared to BAT who had an inadequate response to or had unacceptable side effects from HU. The analysis from RESPONSE to be presented at ASH (Free ASH Whitepaper) shows that patients who received ruxolitinib had greater mean reductions in WBC counts compared with BAT or the HU subgroup of the BAT arm, and these reductions were maintained over time. In patients with baseline WBC counts ≥11×109/L, worsening WBC counts were observed in 10.8 percent of patients in the ruxolitinib arm versus 35.4 percent in the BAT arm (P=0.0002) and 47.8 percent in the HU subgroup (P<0.0001). In this same subgroup of patients with elevated WBC counts at baseline, a greater proportion of patients in the ruxolitinib arm (45%) normalized their WBC counts (achieving a WBC ≤10×109/L or a ≥50% reduction from baseline) compared with BAT (22%) or HU (9%) at week 32. The median time to achieve this response with ruxolitinib therapy was 8 weeks.

These data are scheduled for presentation as a poster session by Dr. Carole Miller, Saint Agnes Cancer Institute, Monday, December 7, 2015, 6:00-8:00 PM EST, Hall A.

About Myelofibrosis
MF is part of a group of related rare blood cancers known as myeloproliferative neoplasms (MPNs) where a patient’s bone marrow can no longer produce enough normal blood cells, causing the spleen to enlarge1. As a result, patients with MF may suffer from debilitating symptoms and have a poor quality of life2. After diagnosis, patients with MF have a decreased life expectancy, with an average survival of approximately five to six years3. Although allogeneic stem cell transplantation may cure MF, the procedure is associated with significant morbidity and transplant-related mortality, and is available to less than 5% of patients who are young and fit enough to undergo the procedure4.

About Polycythemia Vera
Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) and is typically characterized by elevated hematocrit, the volume percentage of red blood cells in whole blood, which can lead to a thickening of the blood and an increased risk of blood clots, as well as an elevated white blood cell and platelet count5. Patients with PV who fail to consistently maintain appropriate blood count levels, including appropriate hematocrit levels, have an approximately four times higher risk of major thrombosis (blood clots) or cardiovascular death6. Patients with PV can also suffer from an enlarged spleen and a significant symptom burden which may be attributed to thickening of the blood and lack of oxygen to parts of the body7. These symptoms commonly include fatigue, itching, night sweats, bone pain, fever, and weight loss8.

Approximately 100,000 patients in the U.S. are living with PV9. Current standard treatment for PV is phlebotomy (the removal of blood from the body) plus aspirin. When phlebotomy can no longer control PV, chemotherapy such as hydroxyurea, or interferon, is utilized10,11. Approximately one in four patients with PV are considered uncontrolled12,13 because they have an inadequate response to or are intolerant of hydroxyurea, the most commonly used chemotherapeutic agent for the treatment of PV.

About Jakafi (ruxolitinib)

Jakafi is a first-in-class JAK1/JAK2 inhibitor approved by the U.S. Food and Drug Administration, for treatment of people with polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea.

Jakafi is also indicated for treatment of people with intermediate or high-risk myelofibrosis (MF), including primary MF, post–polycythemia vera MF, and post–essential thrombocythemia MF.

Jakafi is marketed by Incyte in the United States and by Novartis as Jakavi (ruxolitinib) outside the United States.

Important Safety Information

Jakafi can cause serious side effects, including:
Low blood counts: Jakafi may cause your platelet, red blood cell, or white blood cell counts to be lowered. If you develop bleeding, stop taking Jakafi and call your healthcare provider. Your healthcare provider will perform blood tests to check your blood counts before you start Jakafi and regularly during your treatment. Your healthcare provider may change your dose of Jakafi or stop your treatment based on the results of your blood tests. Tell your healthcare provider right away if you experience unusual bleeding, bruising, fatigue, shortness of breath, or a fever.

Infection: You may be at risk for developing a serious infection during treatment with Jakafi. Tell your healthcare provider if you develop any of the following symptoms of infection: chills, nausea, vomiting, aches, weakness, fever, painful skin rash or blisters.
Skin cancers: Some people who take Jakafi have developed certain types of non-melanoma skin cancers. Tell your healthcare provider if you develop any new or changing skin lesions.

The most common side effects of Jakafi include: anemia, low platelet count, bruising, dizziness, headache.
These are not all the possible side effects of Jakafi. Ask your pharmacist or healthcare provider for more information. Tell your healthcare provider about any side effect that bothers you or that does not go away.

Before taking Jakafi, tell your healthcare provider about all the medications, vitamins, and herbal supplements you are taking and all your medical conditions, including if you have an infection, have or had tuberculosis (TB), or have been in close contact with someone who has TB, have or had liver or kidney problems, are on dialysis, had skin cancer or have any other medical condition. Take Jakafi exactly as your healthcare provider tells you. Do not change or stop taking Jakafi without first talking to your healthcare provider. Do not drink grapefruit juice while on Jakafi.

Women should not take Jakafi while pregnant or planning to become pregnant, or if breast-feeding.

Full Prescribing Information, including a more complete discussion of the risks associated with Jakafi, is available at www.jakafi.com.

On December 5, 2015 Novartis reported that five-year treatment with Jakavi (ruxolitinib) suggested an overall survival advantage for patients with myelofibrosis (MF), despite crossover to Jakavi from the best available therapy arm after the primary analysis at 48 weeks (intent-to-treat analysis: 33% reduction in risk of death, hazard ratio=0.67 [95% confidence interval (CI), 0.44-1.02], crossover-corrected hazard ratio=0.44 [95% CI, 0.18-1.04]) (Press release, Novartis, DEC 5, 2015, View Source [SID:1234508421]). In the COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) Phase III study, more than half of the patients with MF (53.4%) also experienced significant reductions (>=35%) in spleen size with Jakavi therapy, and sustained this benefit over prolonged periods of time (median duration of 3.2 years)[1]. Findings from this study were presented at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting (ASH) (Free ASH Whitepaper) in Orlando, Florida.

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"Given that patients with myelofibrosis have shortened survival expectations and are at an increased risk of complications, the five-year findings from COMFORT-II demonstrate a long-term benefit with Jakavi therapy that is meaningful to the community," said Claire Harrison, MD, study investigator and Consultant Hematologist, Guy’s and St. Thomas’ NHS Foundation Trust, London. "These data help to confirm the important role Jakavi plays in these difficult-to-treat patients."

In addition to the Jakavi data presented at ASH (Free ASH Whitepaper), Novartis announced that a separate Phase III study met its primary endpoint-patients with polycythemia vera (PV) resistant to or intolerant of hydroxyurea who did not have an enlarged spleen who were treated with Jakavi maintained hematocrit control without the need for phlebotomy. In the Phase III RESPONSE 2 (Randomized Study of Efficacy and Safety in POlycythemia Vera with JAK INhibitor Ruxolitinib VerSus BEst Available Care) study, the safety profile of Jakavi was consistent with previous studies. Full results from the trial continue to be evaluated and will be presented at a future medical congress.

"The growing body of research confirms the benefit of Jakavi for patients with rare blood cancers, such as myelofibrosis and polycythemia vera, who have limited treatment options," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "In addition to exhibiting long-term benefits in myelofibrosis, Jakavi also showed potential to benefit a broader population of patients with polycythemia vera, bringing hope to another underserved patient community."

About the COMFORT-II Study
COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) is a randomized, open-label, Phase III study of 219 patients with primary MF, post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF) in 56 study locations in Europe. Two-thirds of patients (146) received Jakavi twice daily and one-third of patients (73) received best available therapy, which was administered at doses and schedules determined by the investigator. Best available therapy was selected by the investigator for each patient and could have included a combination of available agents to treat the disease and/or its symptoms. Of the patients on the best available therapy arm, 61.6% crossed over to receive Jakavi upon protocol-defined progression following the primary analysis after week 48. All patients randomized to best available therapy have crossed over or discontinued. An analysis of the study at five years was performed to evaluate the safety and efficacy of Jakavi in patients with MF[1].

In the Phase III trial, fibrosis grades, a key indicator of disease control in MF, improved (15.8%) or were maintained (32.2%) in nearly half of patients with long-term Jakavi treatment. Nearly one-quarter of patients (26.7% from Jakavi treatment arm; 24.4% who crossed over from best available treatment arm) remained on treatment with Jakavi for five years. All adverse events (AEs) were consistent with previous analyses of treatment with Jakavi in patients with MF. The most common AEs in Jakavi-treated patients either after randomization or after crossing over from best available therapy were thrombocytopenia (52.4%), anemia (49.2%), diarrhea (35.6%) and peripheral edema (33.0%). The most common grade 3/4 AEs included anemia (22.5%), thrombocytopenia (15.2%), pneumonia (5.8%), general physical health deterioration (4.2%) and shortness of breath (4.2%)[1].

About the RESPONSE 2 Study
RESPONSE 2 (Randomized Study of Efficacy and Safety in POlycythemia Vera with JAK INhibitor Ruxolitinib VerSus BEst Available Care) is a multi-center, open label, randomized, Phase IIIb study evaluating the efficacy and safety of Jakavi versus best available therapy. The trial randomized 149 patients with PV who were resistant to or intolerant of hydroxyurea, dependent on phlebotomy for hematocrit control and did not have an enlarged spleen. Patients were randomized 1:1, by stratification (based on hydroxyurea resistance or intolerance) to receive either Jakavi (10 mg twice daily) or best available therapy, which was defined as investigator selected monotherapy or observation only. The dose was adjusted as needed throughout the study.

About Myelofibrosis
MF is part of a group of related rare blood cancers known as myeloproliferative neoplasms (MPNs) where a patient’s bone marrow can no longer produce enough normal blood cells, causing the spleen to enlarge[2]. As a result, patients with MF may suffer from debilitating symptoms and have a poor quality of life[4]. After diagnosis, patients with MF have a decreased life expectancy, with an average survival of approximately five to six years[5]. Although allogeneic stem cell transplantation may cure MF, the procedure is associated with significant morbidity and transplant-related mortality, and is available to less than 5% of patients who are young and fit enough to undergo the procedure[6].

About Polycythemia Vera
Also an MPN, PV is associated with an overproduction of blood cells in the bone marrow and affects roughly one to three people per 100,000 globally[3],[7]. The disease is driven by the dysregulation of the JAK-STAT pathway[8]. It is typically characterized by elevated hematocrit, the volume percentage of red blood cells in whole blood, which can lead to a thickening of the blood and an increased risk of blood clots, as well as an elevated white blood cell and platelet count[3]. This can cause serious cardiovascular complications, such as stroke and heart attack, resulting in increased morbidity and mortality[9]. Approximately 60 to 70% of patients with PV do not have enlarged spleen[10].

A common PV treatment includes phlebotomy, a procedure to remove blood from the body to reduce the concentration of red blood cells, which is used to help maintain a hematocrit level below 45%[3],[9]. However, for a subset of patients, including those with high-risk PV, phlebotomy is usually unsuitable as a permanent treatment option due to its inability to control symptoms or effectively manage the overproduction of red blood cells, therefore cytoreductive agents, such as hydroxyurea, may be added[9]. For patients requiring phlebotomy in combination with hydroxyurea, hematocrit may fluctuate and remain at unsafe levels for significant periods of time[11]. Unfortunately, approximately 25% of patients with PV become resistant to or intolerant of hydroxyurea treatment according to European LeukemiaNet (ELN) criteria, resulting in inadequate disease control and an increased risk of progression[12].

About Jakavi
Jakavi (ruxolitinib) is an oral inhibitor of the JAK 1 and JAK 2 tyrosine kinases. Jakavi is approved by the European Commission for the treatment of adult patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea and for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (MF) (also known as chronic idiopathic MF), post-polycythemia vera MF or post-essential thrombocythemia MF. Jakavi is approved in more than 95 countries for patients with MF, including countries in the European Union, Canada, Japan and countries in Asia, Latin and South America, and in 49 countries for patients with PV, including countries in the European Union, Japan and Canada. The exact indication for Jakavi varies by country. Additional worldwide regulatory filings are underway in MF and PV.

Novartis licensed ruxolitinib from Incyte Corporation for development and commercialization outside the United States. Jakavi is marketed in the United States by Incyte Corporation as Jakafi for the treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea and for the treatment of patients with intermediate or high-risk MF.

The recommended starting dose of Jakavi in PV is 10 mg given orally twice daily. The recommended starting dose of Jakavi in MF is 15 mg twice daily for patients with a platelet count between 100,000 cubic millimeters (mm3) and 200,000 mm3, and 20 mg twice daily for patients with a platelet count of >200,000 mm3. Doses may be titrated based on safety and efficacy. There is limited information to recommend a starting dose for MF and PV patients with platelet counts between 50,000/mm3 and <100,000/mm3. The maximum recommended starting dose in these patients is 5 mg twice daily, and patients should be titrated cautiously[13].

Jakavi is a registered trademark of Novartis AG in countries outside the United States. Jakafi is a registered trademark of Incyte Corporation. The safety and efficacy profile of Jakavi has not yet been established outside the approved indications.

Jakavi Important Safety Information for Treatment of Myelofibrosis (MF) and Polycythemia Vera (PV)
Jakavi can cause serious side effects, including a decrease in blood cell count and infections. Complete blood count monitoring is recommended. Dose reduction or interruption may be required in patients with any hepatic impairment or severe renal impairment or in patients developing hematologic adverse reactions such as thrombocytopenia, anemia and neutropenia. Dose reductions are also recommended when Jakavi is co-administered with strong CYP3A4 inhibitors or fluconazole. Use of Jakavi during pregnancy is not recommended, and women should avoid becoming pregnant during Jakavi therapy. Women taking Jakavi should not breast feed. Progressive multifocal leukoencephalopathy (PML) has been reported. Physicians should be alert for neuropsychiatric symptoms suggestive of PML. Hepatitis B viral load (HBV-DNA titer) increases have been reported in patients with chronic HBV infections. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines. Non-melanoma skin cancer (NMSC) has been reported in Jakavi treated patients. Periodic skin examination is recommended. Very common adverse reactions in MF (>10%) include urinary tract infections, anemia, thrombocytopenia, neutropenia, hypercholesterolemia, dizziness, headache, alanine aminotransferase increased, aspartate aminotransferase increased, bruising and weight gain. Common adverse reactions in MF (1 to 10%) include herpes zoster and flatulence. Uncommon adverse reactions in MF include tuberculosis. Very common adverse reactions in PV (>10%) include anemia, thrombocytopenia, hypercholesterolemia, hypertriglyceridemia, dizziness, alanine aminotransferase increased and aspartate aminotransferase increased. Common adverse reactions in PV (1 to 10%) include urinary tract infections, herpes zoster, weight gain, constipation and hypertension.

On December 5, 2015 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported updated data from the pivotal CLL11 study confirming that Gazyva (obinutuzumab) plus chlorambucil reduced the risk of disease worsening or death by more than half compared to Rituxan (rituximab) plus chlorambucil (progression-free survival, PFS; HR=0.46, median PFS 28.7 months versus 15.7 months; p<0.0001) (Press release, Genentech, DEC 5, 2015, View Source [SID:1234508546]). New results to be presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting from a secondary endpoint that measured time to next treatment (TTNT) showed that, after completing the set six-month Gazyva regimen, people remained treatment-free for nearly four years on average before needing the next treatment for their cancer (TTNT; 51.1 months, including the six-month initial treatment period). No unexpected safety signals were observed with Gazyva.

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"These updated CLL11 data confirmed that Gazyva helped people with previously untreated chronic lymphocytic leukemia live significantly longer without disease worsening or death compared to Rituxan," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "After a fixed course of therapy with Gazyva, people remained treatment-free for nearly four years on average. Time free from treatment is an important consideration for a disease like CLL, which occurs in older adults who frequently have other health issues. "

In the GREEN safety study, data from a subgroup analysis showed there were no unexpected safety signals when Gazyva was combined with bendamustine. In addition, nearly 80 percent of people responded to treatment with Gazyva plus bendamustine (overall response rate, ORR), and a third of people (32.3 percent) achieved a complete response (CR). A substantial number of people were also minimal residual disease (MRD)-negative when measured in the bone marrow or blood (28 percent and 59 percent, respectively), which means no cancer can be detected using a specific test. ORR and MRD-negativity were secondary endpoints of the study.

Gazyva in combination with chlorambucil is approved in the United States for use in people with previously untreated CLL and in the EU for use in people with previously untreated CLL who have co-existing medical conditions (comorbidities) making them unsuitable for an intensive therapy (full-dose fludarabine based therapy).

About the CLL11 Study

CLL11 is a Phase III, multicenter, open-label, randomized three-arm study investigating the efficacy and safety profile of Gazyva plus chlorambucil, Rituxan plus chlorambucil and chlorambucil alone in 781 people with previously untreated CLL. Stage 1 (n=589) compared Gazyva plus chlorambucil to chlorambucil alone and Rituxan plus chlorambucil to chlorambucil alone. Stage 2 (n=663) compared Gazyva plus chlorambucil with Rituxan plus chlorambucil.

The primary endpoint of the study was PFS and secondary endpoints included ORR, overall survival (OS), CR, response duration, disease free survival (DFS), TTNT, MRD-negativity and safety profile.

The updated analysis from CLL11 will be presented at a poster session on Saturday, December 5 at 5:30 P.M. EST (Abstract #1733).

About the GREEN Study

GREEN is an ongoing Phase IIIb safety study. This multicenter, open-label, single-arm study is evaluating the safety and efficacy of Gazyva alone or in combination with chemotherapy, including bendamustine, in people with previously untreated or relapsed/refractory CLL. The primary endpoint of the study was safety with secondary endpoints including ORR and MRD-negativity.

The study included a subgroup of people who were previously untreated and who received treatment with Gazyva in combination with bendamustine. Data from this subgroup analysis will be presented at an oral presentation on Monday, December 7 at 7:00 A.M. EST (Abstract #493).

About Chronic Lymphocytic Leukemia (CLL)

CLL is one of the most common forms of blood cancer and in 2015, it is expected that there will be about 4,650 deaths from CLL in the United States. Most cases of CLL (95 percent) start in white blood cells called B-cells that have a protein called CD20 on their surface.

About Gazyva

Gazyva is an engineered monoclonal antibody designed to attach to CD20, a protein found only on B-cells. It attacks targeted cells both directly and together with the body’s immune system. Gazyva is thought to have an increased ability to induce direct cell death and induces greater activity in how it recruits the body’s immune system to attack B-cells (antibody dependent cellular cytotoxicity; ADCC) when compared to Rituxan. Gazyva was discovered by Roche Glycart AG, a wholly owned, independent research unit of Roche. In the United States, Gazyva is part of a collaboration between Genentech and Biogen Idec.

Gazyva is being studied in a large clinical program, including the Phase III GOYA and GALLIUM studies. GOYA is comparing Gazyva head-to-head with Rituxan plus chemotherapy in first line diffuse large B-cell lymphoma (DLBCL) and GALLIUM is comparing Gazyva plus chemotherapy head-to-head with Rituxan plus chemotherapy in first line indolent non-Hodgkin’s lymphoma (NHL). Additional combination studies investigating Gazyva with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, are planned or underway across a range of blood cancers.

Gazyva Indication

Gazyva is a prescription medicine used with the chemotherapy drug, chlorambucil, to treat chronic lymphocytic leukemia (CLL) in adults who have not had previous CLL treatment.

Important Safety Information

Patients must tell their doctor right away about any side effects they experience.

Gazyva can cause side effects that can become serious or life threatening, including:

Hepatitis B Virus (HBV): Hepatitis B can cause liver failure and death. If a patient has had history of hepatitis B infection, Gazyva could cause it to return. Patients should not receive Gazyva if they have active hepatitis B liver disease. The patient’s doctor or healthcare team will need to screen for hepatitis B before, and monitor the patient for hepatitis during and after, treatment with Gazyva. Sometimes this will require treatment for hepatitis B. Symptoms of hepatitis include: worsening of fatigue and yellow discoloration of skin or eyes.

Progressive Multifocal Leukoencephalopathy (PML): PML is a rare and serious brain infection caused by a virus. PML can be fatal. A patient’s weakened immune system could put the patient at risk. The patient’s doctor will watch for symptoms. Symptoms of PML include: confusion, difficulty talking or walking, dizziness or loss of balance, and vision problems.

Additional possible serious side effects of Gazyva:

Patients must tell their doctor right away about any side effects they experience. Gazyva can cause side effects that may become severe or life threatening, including:

Infusion Reactions: These side effects may occur during or within 24 hours of any Gazyva infusion. Some infusion reactions can be serious, including, but not limited to, severe allergic reactions (anaphylaxis), acute life-threatening breathing problems, or other life-threatening infusion reactions. If a patient has a reaction, the infusion is either slowed or stopped until the patient’s symptoms are resolved. Most patients are able to complete infusions and receive medication again. However, if the infusion reaction is serious, the infusion of Gazyva will be permanently stopped. The patient’s healthcare team will take steps to help lessen any side effects the patient may have to the infusion process. The patient may be given medicines to take before each Gazyva treatment. Signs of infusion reactions may include: dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, and chest pain.
Tumor Lysis Syndrome (TLS): Gazyva works to break down cancer cells quickly.
As cancer cells break apart, their contents are released into the blood. These contents may cause damage to organs and the heart, and may lead to kidney failure requiring the need for dialysis treatment. TLS, including death, has been reported in patients receiving Gazyva. The patient’s doctor may prescribe medication to help prevent TLS. The patient’s doctor will also conduct regular blood tests to check for TLS. Symptoms of TLS may include nausea, vomiting, diarrhea, and tiredness.

Infections: While a patient is taking Gazyva, the patient may develop infections. Some of these infections may be severe. Fatal infections have been reported, so the patient should be sure to talk to the doctor if the patient thinks the patient has one. Patients with active infection should not be treated with Gazyva. Infections may continue even after the patient stops taking Gazyva. The patient’s doctor may prescribe medications to help prevent infections. Symptoms of infection include fever and cough.
Low White Blood Cell Count : When a patient has an abnormally low count of infection-fighting white blood cells, it is called neutropenia. While the patient is taking Gazyva, the patient’s doctor will do blood work to check the patient’s white blood cell counts. Neutropenia can develop during or after treatment with Gazyva. It may also last for more than one month. If a patient’s white blood cell count is low, the patient’s doctor may prescribe medication to help prevent infections.
Low Platelet Count: Platelets help stop bleeding or blood loss. Gazyva may reduce the number of platelets the patient has in the blood. This may affect the clotting process. While the patient is taking Gazyva, the patient’s doctor will do blood work to check the patient’s platelet count.
Most common side effects of Gazyva

The most common side effects of Gazyva are infusion reactions, low white blood cell counts, low platelet counts, low red blood cell counts, fever, cough, nausea, and diarrhea.

Before receiving Gazyva, patients should talk to their doctor about:

Immunizations: Before receiving Gazyva therapy, the patient should tell the patient’s healthcare provider if the patient has recently received or is scheduled to receive a vaccine. Patients who are treated with Gazyva should not receive live vaccines.

Pregnancy: A patient should tell the doctor if the patient is pregnant, plans to become pregnant, or is breastfeeding. Gazyva may harm the unborn baby. Mothers who have been exposed to Gazyva during pregnancy should discuss the safety and timing of live virus vaccinations for their infants with their child’s healthcare providers. It is not known if Gazyva may pass into the patient’s breast milk. The patient should speak to the doctor about using Gazyva if the patient is breastfeeding.

Patients must tell their doctor about any side effects.

These are not all of the possible side effects of Gazyva. For more information, patients should ask their doctor or pharmacist.

Gazyva is available by prescription only.

Report side effects to the FDA at (800) FDA-1088, or View Source Report side effects to Genentech at (888) 835-2555.

Please visit View Source for the full Prescribing Information, including

Boxed WARNINGS, for additional Important Safety Information.

Rituxan Indications

Rituxan (rituximab) is indicated for the treatment of patients with:

· Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent

· Previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy and, in patients achieving a complete or partial response to Rituxan in combination with chemotherapy, as single-agent maintenance therapy

· Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after first-line CVP chemotherapy

· Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens

· Previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide (FC)

Rituxan is not recommended for use in patients with severe, active infections.

Important Safety Information:

Rituxan can cause serious side effects that can lead to death, including:

Infusion Reactions: may occur during or within 24 hours of the infusion. The
patient’s doctor should give the patient medicines before their treatment. Symptoms can include hives, rash, itching, facial or oral swelling, sudden cough, shortness of breath, difficulty breathing, weakness, dizziness, feeling faint, racing heart or chest pain.

Severe Skin and Mouth Reactions: symptoms can include painful sores, ulcers, or blisters on the skin, lips or mouth; peeling skin; rash; or pustules.

Hepatitis B Virus (HBV) Reactivation: may cause serious liver problems including liver failure and death. If patients have had hepatitis B or are carriers of HBV, receiving Rituxan could cause the virus to become an active infection again. Patient should not receive Rituxan if they have active HBV liver disease. The patient’s doctor will do blood tests to check for HBV infection prior to treatment and will monitor the patient during and for several months following their treatment.

Progressive Multifocal Leukoencephalopathy (PML): a rare, serious brain infection that can lead to severe disability and death and for which there is no known prevention, treatment or cure. Symptoms can include difficulty thinking, loss of balance, changes in speech or walking, weakness on one side of the body or blurred or lost vision.

What are the additional possible serious side effects of Rituxan?

Patients must tell their doctor right away about any side effects they experience. Rituxan can cause serious side effects that can lead to death, including:

Tumor Lysis Syndrome (TLS): may cause kidney failure and the need for dialysis treatment, abnormal heart rhythm and can lead to death. The patient’s doctor may give the patient medicines before their treatment to help prevent TLS.
Serious Infections: can happen during and after treatment and can lead to
death. These infections may be bacterial, fungal or viral. Symptoms can include fever; cold or flu symptoms; earache or headache; pain during urination; white patches in the mouth or throat; cuts or scrapes that are red, warm, swollen or painful.

Heart Problems: symptoms can include chest pain and irregular heartbeats that may require treatment. The patient’s doctor may need to stop their treatment.

Kidney Problems: the patient’s doctor should do blood tests to check how well the patient’s kidneys are working.

Stomach and Serious Bowel Problems: can include blockage or tears in the bowel that can lead to death. Stomach area pain during treatment can be a symptom.

Low Blood Cell Counts: the patient’s blood cell counts may be monitored during treatment.

The most common side effects of Rituxan are infusion reactions, chills, infections, body aches, tiredness and low white blood cells.

Patients must tell their doctor if they are pregnant, plan to become pregnant or are breastfeeding. It is not known if Rituxan may harm the patient’s unborn baby or pass into the patient’s breast milk. Women should use birth control while using Rituxan and for 12 months after treatment.

Patients must tell their doctor about any side effect that bothers them or that does not go away.

These are not all of the possible side effects of Rituxan. For more information, patients should ask their doctor or pharmacist.

On December 5, 2015 Celgene Corporation (NASDAQ:CELG) and Acceleron Pharma Inc. (NASDAQ:XLRN) reported preliminary results from an ongoing long-term Phase 2 extension study in patients with lower risk myelodysplastic syndromes (MDS) at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Acceleron Pharma, DEC 5, 2015, View Source [SID:1234508405]). Results highlighted in an oral presentation showed that patients with lower risk MDS treated with luspatercept in the long-term extension study achieved and maintained increased hemoglobin levels and transfusion independence. Celgene and Acceleron are jointly developing luspatercept.

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"These results for longer-term luspatercept treatment in lower risk MDS patients are very exciting," said Aristoteles Giagounidis, M.D., Ph.D., Head of the Department of Oncology, Haematology, and Palliative Care at Marien Hospital in Düsseldorf, Germany. "There is substantial unmet medical need for patients who do not respond or become refractory to treatment with erythropoiesis stimulating agents or who are considered ineligible to receive them. Luspatercept has shown very encouraging activity in these patients which provides the basis for the Phase 3 MEDALIST study."

Luspatercept Data Presented at ASH (Free ASH Whitepaper)

A total of 32 low- or intermediate-1 risk MDS patients were treated with luspatercept in this long-term 24-month open-label extension study. Luspatercept was administered subcutaneously once every 3 weeks at a starting dose level of 1.0 mg/kg. The dose level could be increased to 1.75 mg/kg. Of these 32 patients, 13 had a low transfusion burden ( < 4 units RBC/8 weeks) and 19 had a high transfusion burden (≥4 units RBC/8 weeks). 59% of patients had been treated previously with erythropoiesis stimulating agents (ESA) and 19% of patients had previously been treated with lenalidomide. 91% of the patients were ring sideroblast positive (more than 15% of erythroid cells in the bone marrow were ring sideroblasts).

Patients who were refractory or intolerant to prior ESA treatment

63% (12 of 19) of HTB and LTB patients with prior ESA treatment achieved an International Working Group (IWG) Hematologic Improvement Erythroid (HI-E) response of a reduction of ≥4 units RBC over 8 weeks or a hemoglobin increase ≥1.5 g/dL for ≥8 weeks during their luspatercept treatment period
50% (7 of 14) achieved transfusion independence

Patients who are considered ESA ineligible because they had elevated erythropoietin levels between 200 and 500 U/L

71% (5 of 7) achieved an HI-E response and 50% (2 of 4) achieved transfusion independence

High Transfusion Burden (HTB) Patients

68% (13 of 19) of the HTB patients achieved the IWG HI-E criteria of a reduction of ≥4 units RBC over 8 weeks
42% (8 of 19) of the HTB patients achieved transfusion independence for ≥8 weeks

Low Transfusion Burden (LTB) Patients

69% (9 of 13) of the LTB patients achieved the IWG HI-E response criteria of a hemoglobin increase ≥1.5 g/dL for ≥8 weeks
The mean increase in hemoglobin reached levels between 2.0 and 2.5 g/dL and was maintained for the 9 months for which data are available

Safety

Adverse events at least possibly related to study drug that occurred in patients during the extension study included bone pain, headache, hypotonia, myalgia and nausea. No serious or grade 3 or 4 adverse events related to study drug have been reported during the ongoing extension study.
Celgene and Acceleron are in the process of initiating a global Phase 3 study in low risk, ring sideroblast positive MDS patients.

Luspatercept is an investigational product that is not approved for any use in any country.

About Luspatercept

Luspatercept is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members in the Transforming Growth Factor-Beta (TGF-β) superfamily involved in the late stages of erythropoiesis (red blood cell production). Luspatercept regulates late-stage erythrocyte (red blood cell) precursor cell differentiation and maturation. This mechanism of action is distinct from that of erythropoietin (EPO), which stimulates the proliferation of early-stage erythrocyte precursor cells. Acceleron and Celgene are jointly developing luspatercept as part of a global collaboration. For more information, please visit www.clinicaltrials.gov.

On December 5, 2015 Amgen (NASDAQ:AMGN) reported that The Lancet Oncology published results from the pivotal Phase 3 head-to-head ENDEAVOR study comparing Kyprolis (carfilzomib) plus dexamethasone to Velcade (bortezomib) plus dexamethasone in patients with relapsed multiple myeloma (Press release, Amgen, DEC 5, 2015, View Source;p=RssLanding&cat=news&id=2120388 [SID:1234508408]). The data showed that patients treated with Kyprolis plus dexamethasone achieved progression-free survival (PFS) of 18.7 months compared to 9.4 months in those receiving bortezomib plus dexamethasone (HR=0.53; 95 percent CI: 0.44,0.65 p<0.0001), a current standard of care in relapsed multiple myeloma.

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These findings demonstrate that patients with relapsed multiple myeloma treated with Kyprolis lived twice as long without disease worsening as those treated with bortezomib. The most common adverse events (greater than 25 percent) in the Kyprolis arm were diarrhea, anemia, fatigue, dyspnea, pyrexia and insomnia. Treatment discontinuation due to adverse events and on-study deaths were comparable between the two arms.

To view the multimedia assets associated with this press release, please click: View Source

"In this head-to-head comparison, carfilzomib plus dexamethasone resulted in a twofold decrease in the risk of progression or death, compared with bortezomib plus dexamethasone, a result that was consistent regardless of age or prior bortezomib exposure," said study co-author and investigator, Meletios A. Dimopoulos, M.D., professor of Clinical Therapeutics at the National and Kapodistrian University of Athens, School of Medicine. "For patients with multiple myeloma, these results are clinically meaningful and translate to more than nine months without disease progression."

"Coupled with results previously seen in the ASPIRE pivotal trial, data from the ENDEAVOR study support the use of Kyprolis as a backbone therapy for the management of relapsed multiple myeloma, a difficult-to-treat blood cancer," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "This is an important publication because it provides clinical evidence of Kyprolis’ potential to extend the time patients live without their disease progressing and improve the depth and duration of a response."

Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse, and while new therapies have become available, a significant unmet need still remains for patients no longer responding to treatment.1,2 Multiple myeloma is an orphan disease and accounts for approximately one percent of all cancers.3,4

Regulatory Status
Data from the ENDEAVOR study are the basis of the supplemental New Drug Application (sNDA) of Kyprolis in combination with dexamethasone for patients with relapsed multiple myeloma. The sNDA was accepted Sept.19, 2015, for priority review by the U.S. Food and Drug Administration (FDA) and the Prescription Drug User Fee Act (PDUFA) target action date is Jan. 22, 2016. Priority review is assigned to applications for drugs that treat serious conditions and would, if approved, provide significant improvements in the safety or effectiveness of the treatment, diagnosis or prevention of serious conditions. Amgen also just announced submission of the ENDEAVOR data to the European Commission for potential authorization of Kyprolis in combination with dexamethasone in the European Union.

About ENDEAVOR
The randomized ENDEAVOR (RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma) trial of 929 patients evaluated Kyprolis in combination with low-dose dexamethasone, versus bortezomib with low-dose dexamethasone in patients whose multiple myeloma has relapsed after at least one, but not more than three prior therapeutic regimens. The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. In a clinical trial, measuring the PFS is one way to demonstrate how well a treatment works.5

The superiority of the Kyprolis combination compared to the bortezomib combination with respect to PFS was seen across all pre-specified subgroups, including Velcade-naïve patients, those with high- or standard-risk cytogenetics and with or without prior transplantation. The Kyprolis combination also demonstrated superiority over the bortezomib combination for secondary endpoints, achieving a higher overall response rate (76.9 percent vs. 62.6 percent; p<0.0001) and lower rate of grade 2 or higher neuropathy events (6 percent vs. 32 percent; p<0.0001). Treatment with the Kyprolis combination resulted in a two-fold increase in the median duration of response (21.3 months) compared to the bortezomib combination (10.4 months).

In the Kyprolis and bortezomib groups, 54.3 percent and 28.6 percent of patients achieved a very good partial response or better (p<0.0001), and 12.5 percent and 6.2 percent of patients achieved a complete response or better (p<0.0001), respectively. Overall survival data are not yet mature and continue to be monitored.

Treatment discontinuation due to adverse events and on-study deaths were comparable between the two arms. A number of known adverse drug reactions were reported at a higher rate in the Kyprolis group compared with the bortezomib group, including any-grade dyspnea, hypertension, pyrexia, and cough (preferred terms) as were any-grade cardiac failure (grouped term; 8.2 percent vs. 2.9 percent) and acute renal failure (grouped term; 8.2 percent vs. 4.8 percent). However, the rates of cardiac and renal failure for Kyprolis were comparable to those observed in the previous Phase 3 ASPIRE study.

Rates of grade 3 or higher adverse events were 73.2 percent in the Kyprolis group and 66.9 percent in the bortezomib group. Grade 3 or higher adverse events of interest in the Kyprolis and bortezomib groups included hypertension (preferred term; 8.9 percent vs. 2.6 percent), dyspnea (preferred term; 5.4 percent vs. 2.2 percent), cardiac failure (grouped term; 4.7 percent vs. 1.8 percent), acute renal failure (grouped term; 4.0 percent vs. 2.6 percent), ischemic heart disease (grouped term; 1.7 percent vs. 1.6 percent) and pulmonary hypertension (grouped term; 0.6 percent vs. 0.2 percent).

Patients received treatment until progression with Kyprolis as a 30-minute infusion on days 1, 2, 8, 9, 15 and 16 of 28 day treatment cycles, along with low-dose dexamethasone (20 mg). For Cycle 1 only, Kyprolis was administered at 20 mg/m2 on days 1 and 2, followed by escalation to 56 mg/m2 from day 8. Patients who tolerated 56 mg/m2 in Cycle 1 were kept at this dose for subsequent cycles. Patients who received bortezomib (1.3 mg/m2) with low-dose dexamethasone (20 mg) were administered bortezomib subcutaneously or intravenously at the discretion of the investigator and in accordance with regulatory approval of bortezomib. More than 75 percent of the patients in the control arm received bortezomib subcutaneously. This study was conducted at 235 sites worldwide. For information about this trial, please visit www.clinicaltrials.gov under trial identification number NCT01568866.

Amgen Webcast Investor Meeting
Amgen will host a webcast investor meeting at the 57th Anuual American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting on Monday, Dec. 7, 2015, at 7 p.m. ET. Sean E. Harper, M.D., executive vice president of Research and Development at Amgen, along with members of Amgen’s clinical development team and clinical investigators will participate to discuss data presented at ASH (Free ASH Whitepaper) and Amgen’s broader oncology portfolio of products.

Live audio of the conference call will be simultaneously broadcast over the Internet and will be available to members of the news media, investors and the general public.

The webcast, as with other selected presentations regarding developments in Amgen’s business given by management at certain investor and medical conferences, can be found on Amgen’s website, www.amgen.com, under Investors. Information regarding presentation times, webcast availability and webcast links are noted on Amgen’s Investor Relations Events Calendar. The webcast will be archived and available for replay for at least 90 days after the event.

About Kyprolis (carfilzomib) for Injection
Kyprolis is an irreversible proteasome inhibitor for use in the treatment of patients with relapsed multiple myeloma.2 Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.6 Kyprolis has been shown to block proteasomes, leading to an excessive build-up of proteins within cells.7 In some cells, Kyprolis can cause cell death, especially in myeloma cells because they are more likely to contain a higher amount of abnormal proteins.7 The irreversibility of Kyprolis’ binding has also been shown to offer a more sustained inhibition of the targeted enzymes.8

Kyprolis is currently approved in the U.S. in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior lines of therapy.

Kyprolis is also indicated under FDA accelerated approval as a single agent for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Kyprolis is also approved in Argentina, Israel, Kuwait, Mexico, Thailand, Colombia and the European Union. Additional regulatory applications for Kyprolis are underway and have been submitted to health authorities worldwide.

Kyprolis is a product of Onyx Pharmaceuticals, Inc. Onyx Pharmaceuticals is a subsidiary of Amgen and holds development and commercialization rights to Kyprolis globally, excluding Japan.

For more information about Kyprolis, visit www.kyprolis.com.

Important Safety Information Regarding Kyprolis (carfilzomib) for Injection U.S. Indication

Cardiac Toxicities
New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, and decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of Kyprolis. Death due to cardiac arrest has occurred within a day of Kyprolis administration.

Withhold Kyprolis for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart Kyprolis based on a benefit/risk assessment.

Adequate hydration is required prior to each dose in Cycle 1. Monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure. Patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, and conduction abnormalities may be at greater risk for cardiac complications.

Acute Renal Failure
Cases of acute renal failure and renal insufficiency adverse events (renal impairment, acute renal failure, and renal failure) have occurred in patients receiving Kyprolis. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received Kyprolis monotherapy. This risk was greater in patients with a baseline reduced estimated creatinine clearance. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.

Tumor Lysis Syndrome
Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred in patients receiving Kyprolis. Patients with multiple myeloma and a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly. Withhold Kyprolis until TLS is resolved.

Pulmonary Toxicity
Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving Kyprolis. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue Kyprolis.

Pulmonary Hypertension
Pulmonary arterial hypertension (PAH) was reported in patients treated with Kyprolis. Evaluate with cardiac imaging and/or other tests as indicated. Withhold Kyprolis for PAH until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment.

Dyspnea
Dyspnea was reported in patients treated with Kyprolis. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop Kyprolis for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart Kyprolis based on a benefit/risk assessment.

Hypertension
Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. Some of these events have been fatal. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on a benefit/risk assessment.

Venous Thrombosis
Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. Thromboprophylaxis is recommended and should be based on an assessment of the patient’s underlying risks, treatment regimen, and clinical status.

Infusion Reactions
Infusion reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms of an infusion reaction and to contact a physician immediately if they occur.

Thrombocytopenia
Kyprolis causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was reported in patients receiving Kyprolis. Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate.

Hepatic Toxicity and Hepatic Failure
Cases of hepatic failure, including fatal cases, have been reported during treatment with Kyprolis. Kyprolis can cause increased serum transaminases. Monitor liver enzymes regularly. Reduce or withhold dose as appropriate.

Thrombotic Thrombocytopenic Purpura /Hemolytic Uremic Syndrome (TTP/HUS)
Cases of TTP/HUS including fatal outcome have occurred in patients receiving Kyprolis. Monitor for signs and symptoms of TTP/HUS. Discontinue Kyprolis if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. The safety of reinitiating Kyprolis therapy in patients previously experiencing TTP/HUS is not known.

Posterior Reversible Encephalopathy Syndrome (PRES)
Cases of PRES have occurred in patients receiving Kyprolis. PRES was formerly known as Reversible Posterior Leukoencephalopathy Syndrome. Consider a neuro-radiological imaging (MRI) for onset of visual or neurological symptoms, such as seizure, headache, lethargy, confusion, blindness, altered consciousness, along with hypertension. Discontinue Kyprolis if PRES is suspected and evaluate. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known.

Embryo-fetal Toxicity
Kyprolis can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals.

Females of reproductive potential should be advised to avoid becoming pregnant while being treated with Kyprolis and the potential hazard to the fetus if Kyprolis is used during pregnancy.

ADVERSE REACTIONS
The most common adverse events of any grade occurring in at least 20 percent of patients treated with Kyprolis in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, decreased platelets, dyspnea, diarrhea, decreased lymphocyte, headache, decreased hemoglobin, cough, edema peripheral.

The most common adverse events of any grade occurring in at least 20 percent of patients treated with Kyprolis in the combination therapy trial: decreased lymphocytes, decreased absolute neutrophil count, decreased phosphorus, anemia, neutropenia, decreased total white blood cell count, decreased platelets, diarrhea, fatigue, thrombocytopenia, pyrexia, muscle spasm, cough, upper respiratory tract infection, decreased hemoglobin, hypokalemia.

Full U.S. prescribing information is available at www.kyprolis.com.

Important EU Product Safety Information

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Kyprolis treatment should be supervised by a physician experienced in the use of anti-cancer therapy. The most serious side effects that may occur during Kyprolis treatment include: cardiac toxicity, pulmonary toxicities, pulmonary hypertension, dyspnoea, hypertension including hypertensive crises, acute renal failure, tumour lysis syndrome, infusion reactions, thrombocytopenia, hepatic toxicity, posterior reversible encephalopathy syndrome (PRES) and thrombotic thrombocytopenic purpura/haemolytic uremic syndrome (TTP/HUS). The most common side effects are anaemia, fatigue, diarrhoea, thrombocytopenia, nausea, pyrexia, dyspnoea, respiratory tract infection, cough and peripheral oedema.