On July 12, 2017 Amgen (NASDAQ:AMGN) reported positive results from the final analysis of the Phase 3 ASPIRE trial. The study met the key secondary endpoint of overall survival (OS), demonstrating that KYPROLIS (carfilzomib), lenalidomide and dexamethasone (KRd) reduced the risk of death by 21 percent over lenalidomide and dexamethasone alone (Rd) (median OS 48.3 months for KRd versus 40.4 months for Rd, HR = 0.79, 95 percent CI, 0.67 – 0.95) (Press release, Amgen, JUL 12, 2017, View Source [SID1234519792]). Per protocol, patients received 18 cycles of KYPROLIS with Rd before continuing treatment with Rd alone to progression. This KRd regimen of twice-weekly KYPROLIS administered at 27 mg/m2 is currently approved in the U.S., European Union and other countries based on the primary analysis of progression-free survival (PFS) in the ASPIRE study.

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"For multiple myeloma patients, the first relapse is usually the most devastating," said David S. Siegel, M.D., Ph.D., chief of the Division of Multiple Myeloma at John Theurer Cancer Center in Hackensack, N.J., and investigator on the ASPIRE trial. "These data clearly show that the addition of KYPROLIS – for just 18 cycles – to lenalidomide and dexamethasone at relapse gave patients a significantly improved chance of survival. With these results, this KYPROLIS regimen should be considered a new standard of care."

"The ENDEAVOR study has already demonstrated that KYPROLIS is the superior proteasome inhibitor versus Velcade," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "This overall survival benefit from the ASPIRE trial further supports the importance of proteasome inhibition and duration of treatment with KYPROLIS in the treatment of relapsed multiple myeloma."

Adverse events observed in this updated analysis were consistent with those previously reported for ASPIRE. The most common adverse events (greater than or equal to 20 percent) in the KYPROLIS arm were diarrhea, anemia, neutropenia, fatigue, upper respiratory tract infection, pyrexia, cough, hypokalemia, thrombocytopenia, muscle spasms, pneumonia, nasopharyngitis, nausea, constipation, insomnia and bronchitis.

Amgen recently announced OS results from the Phase 3 head-to-head ENDEAVOR trial, which showed KYPROLIS at 56 mg/m2 in combination with dexamethasone reduced the risk of death by 21 percent over Velcade (bortezomib) and dexamethasone (Vd). Patients treated with KYPROLIS lived 7.6 months longer than those treated with Velcade (median OS 47.6 months for Kd versus 40.0 months for Vd, HR = 0.79, 95 percent CI, 0.65 – 0.96).

The ASPIRE OS data will be submitted to a future medical conference, for publication, and to regulatory agencies worldwide to support a potential label update.

The KYPROLIS clinical program continues to focus on providing solutions for physicians and patients in treating this frequently relapsing and difficult-to-treat cancer. KYPROLIS is available for patients whose myeloma has relapsed or become resistant to another treatment and continues to be studied in a range of combinations and patient populations.

About ASPIRE
The international, randomized Phase 3 ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma) trial evaluated KYPROLIS in combination with lenalidomide and dexamethasone, versus lenalidomide and dexamethasone alone, in patients with relapsed multiple myeloma following treatment with one to three prior regimens. The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. Secondary endpoints included OS, overall response rate (ORR), duration of response (DOR), disease control rate, health-related quality of life (HR-QoL) and safety. Patients were randomized to receive KYPROLIS (20 mg/m2 on days 1 and 2 of cycle one, escalating to 27 mg/m2 on days 8, 9, 15 and 16 of cycle one and continuing on days 1, 2, 8, 9, 15 and 16 of subsequent cycles), in addition to a standard dosing schedule of lenalidomide (25 mg per day for 21 days on, 7 days off) and low-dose dexamethasone (40 mg per week in four-week cycles), versus lenalidomide and low-dose dexamethasone alone. The study randomized 792 patients at sites in North America, Europe and Israel.

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 (Kd), versus bortezomib with low-dose dexamethasone (Vd) 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. The primary analysis was published in The Lancet Oncology and is described in the Prescribing Information.

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 one only, KYPROLIS was administered at 20 mg/m2 on days 1 and 2, and if tolerated was escalated to 56 mg/m2 from day 8 cycle one onwards. Patients who received bortezomib (1.3 mg/m2) with low-dose dexamethasone (20 mg) were treated with bortezomib administered subcutaneously or intravenously at the discretion of the investigator and in accordance with regional 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.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse.1 It is a rare and very aggressive disease that accounts for approximately one percent of all cancers.2,3 In the U.S., there are nearly 95,000 people living with, or in remission from, multiple myeloma.4 Approximately 30,330 Americans are diagnosed with multiple myeloma each year and 12,650 patient deaths are reported on an annual basis.4

About KYPROLIS (carfilzomib)
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.5 KYPROLIS has been shown to block proteasomes, leading to an excessive build-up of proteins within cells.5 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.5,6

KYPROLIS is approved in the U.S. for the following:

In combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
KYPROLIS is also approved in Argentina, Australia, Bahrain, Canada, Hong Kong, Israel, Japan, Kuwait, Lebanon, Macao, Mexico, Thailand, Colombia, S. Korea, Canada, Qatar, Switzerland, United Arab Emirates, Turkey, Russia, Brazil, India, Oman and the European Union. Additional regulatory applications for KYPROLIS are underway and have been submitted to health authorities worldwide.

IMPORTANT SAFETY INFORMATION

Cardiac Toxicities

New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of KYPROLIS administration.
Monitor patients for clinical signs or symptoms of cardiac failure or cardiac ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart KYPROLIS at 1 dose level reduction based on a benefit/risk assessment.
While 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, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment (including blood pressure and fluid management) prior to starting treatment with KYPROLIS and remain under close follow-up.
Acute Renal Failure

Cases of acute renal failure and renal insufficiency adverse events (including 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. 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 for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
Patients using oral contraceptives or a hormonal method of contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment with KYPROLIS in combination with dexamethasone or lenalidomide plus dexamethasone.
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.
Hemorrhage

Fatal or serious cases of hemorrhage have been reported in patients receiving KYPROLIS. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate.
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 regardless of baseline values. Reduce or withhold dose as appropriate.
Thrombotic Microangiopathy

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (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. Discontinue KYPROLIS if PRES is suspected and evaluate. The safety of reinitiating KYPROLIS therapy in patients previously experiencing PRES is not known.
Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-ineligible Patients

In a clinical trial of transplant-ineligible patients with newly diagnosed multiple myeloma comparing KYPROLIS, melphalan, and prednisone (KMP) vs bortezomib, melphalan, and prednisone (VMP), a higher incidence of serious and fatal adverse events was observed in patients in the KMP arm. KYPROLIS in combination with melphalan and prednisone is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma.
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. Males of reproductive potential should be advised to avoid fathering a child while being treated with KYPROLIS. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.
ADVERSE REACTIONS

The most common adverse reactions occurring in at least 20% of patients treated with KYPROLIS in the combination therapy trials: anemia, neutropenia, diarrhea, dyspnea, fatigue, thrombocytopenia, pyrexia, insomnia, muscle spasm, cough, upper respiratory tract infection, hypokalemia.
The most common adverse reactions occurring in at least 20% of patients treated with KYPROLIS in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.
Please see full prescribing information at www.kyprolis.com.

On July 11, 2017 Cytovia Inc. ("Cytovia") the oncology subsidiary of Immune Pharmaceuticals Inc. (NASDAQ: IMNP) ("Immune") reported that it has entered into a licensing agreement with Pint Pharma International S.A. ("Pint") a pharmaceutical company focused on Latin America and other markets, for the marketing and distribution of Ceplene throughout Latin America (the "territory") (Press release, Immune Pharmaceuticals, JUL 11, 2017, View Source [SID1234519793]). Pint Gmbh will separately enter into an investment agreement, which will lead to an investment of $4 million into Cytovia. Dr. Massimo Radaelli, Executive Chairman of Pint, will also join the board of Cytovia upon completion of the investment and effective spin off of Cytovia from Immune.

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"Following the acquisition from Mylan of Ceplene rights in Europe and Asia, Cytovia is pleased to confirm the partnership with Pint for Latin America markets. This will provide Cytovia an opportunity to generate revenues from Latin American sales of Ceplene. This potential is incremental to revenues expected from European sales where Ceplene is approved in thirty countries." said Daniel Teper, of Cytovia.

"We intend to immediately initiate regulatory registration of Ceplene in the LATAM markets based on the European approval. Furthermore, Pint has extensive experience with Early Access Programs for orphan drugs and is planning to offer a similar program to AML patients who are candidates for treatment with Ceplene" added David Munoz, CEO of Pint.

Ceplene is the only drug currently approved in 30 European countries and Israel for the maintenance of first remission in Acute Myeloid Leukemia (AML). Ceplene has a reimbursed cost of therapy of approximately $25,000/year in Europe based on a full course of treatment. The addressable market for remission maintenance in AML is estimated at 7000 patients in Europe. Additionally the addressable market in Latin America is estimated at 4000 patients. There are currently no alternative drugs approved in the remission setting.

About Ceplene
Ceplene (histamine dihydrochloride) is administered in conjunction with low dose interleukin-2 (IL-2), for maintenance of first remission in patients with Acute Myeloid Leukemia (AML). It has been shown in clinical studies to prevent leukemic relapses in AML patients in first remission and prolong leukemia-free survival, while maintaining good quality of life during treatment. Ceplene acts by enhancing the immunostimulatory effect of IL-2 and countering reactive oxygen species-induced dysfunction and apoptosis of T and NK cells, thereby inducing immune-mediated killing of leukemic cells, providing a strong rationale for this combination therapy. A recent Phase IV study presented at the meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) in 2016 confirmed the safety and efficacy of Ceplene in the international study that supported European approval.

About Acute Myeloid Leukemia (AML)
AML patients receive intensive induction treatment with chemotherapeutic drugs at diagnosis and typically become free of detectable leukemia, achieving "complete remission." However, within 1-2 years, the majority (75-80%) of adult patients will experience a relapse of leukemia, with a survival prognosis of 33% in younger patients and 15-20% in patients over 60 years of age. According to the American Cancer Society, there will be approximately 21,380 new cases of AML and 10,590 deaths from AML in the US in 2017. The prognosis following first remission is poor and there are no other effective remission therapies currently available. AML represents an orphan condition with high unmet need.

On July 11, 2017 Pfizer Inc. (NYSE:PFE) reported that the U.S. Food and Drug Administration’s (FDA) Oncologic Drug Advisory Committee (ODAC) voted that the results of ALFA-0701 demonstrated a favorable risk:benefit profile for MYLOTARG (gemtuzumab ozogamicin) 3 mg/m2 on days 1, 4 and 7 added to chemotherapy for patients with newly-diagnosed CD33-positive acute myeloid leukemia (AML) (Press release, Pfizer, JUL 11, 2017, View Source [SID1234519788]). The role of the Advisory Committee is to provide recommendations to the FDA. The FDA decision on whether or not to approve the MYLOTARG application is anticipated by September 2017.

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"We are extremely pleased with the Committee’s recommendation and believe this is an important step toward our goal of making MYLOTARG available to patients with newly-diagnosed AML," said Mace Rothenberg, MD, Chief Development Officer, Oncology, Pfizer Global Product Development. "We look forward to working closely with the FDA as we continue the regulatory process. We are grateful to both the investigators who led MYLOTARG clinical trials and the patients who participated."

The ODAC discussions were based on the Biologics License Application (BLA) currently under review by the FDA. The BLA includes Pfizer-sponsored studies from the original New Drug Application (NDA) for MYLOTARG, an investigator-led Phase 3 randomized, open-label study (ALFA-0701) and an individual patient data meta-analysis from over 3,000 patients in five randomized Phase 3 studies (including ALFA-0701). These studies span 10 years of research and include more than 4,300 patients.

"Clinical studies investigating MYLOTARG have provided a significant body of evidence supporting the risk:benefit profile of MYLOTARG in AML," said Jorge Cortes, MD, University of Texas, MD Anderson Cancer Center. "Based on the totality of the efficacy and safety data, MYLOTARG, if approved, has the potential to be an important treatment option for adult patients with AML."

Due to the critical unmet need for patients with newly-diagnosed AML, there has been great interest among AML investigators to evaluate MYLOTARG in this population using different doses and different schedules of MYLOTARG. These investigator-led clinical trials have provided more information on the efficacy and safety of MYLOTARG.

ODAC is an independent panel of experts that evaluates data concerning the efficacy and safety of marketed and investigational cancer treatments and makes recommendations to the FDA. Its vote is not binding, but is considered by the FDA in its decision-making process.

About AML

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and accounts for approximately 80% of all cases of acute leukemia.1 About 21,380 people are expected to be diagnosed with AML in the United States in 2017.2 Despite recent developments in understanding the scientific basis of AML and its treatment, there has been little progress in increasing the long-term survival rate in AML patients.3 Only one in four patients with AML survive longer than five years.2

About MYLOTARG (gemtuzumab ozogamicin)

MYLOTARG is an investigational antibody-drug conjugate (ADC) comprised of the cytotoxic agent calicheamicin, attached to a monoclonal antibody (mAB) targeting CD33, an antigen expressed on the surface of myeloblasts in more than 90 percent of AML patients.4,5,6 When MYLOTARG binds to the CD33 antigen on the cell surface it is absorbed into the cell and calicheamicin is released causing cell death.4,5

MYLOTARG was originally approved under the FDA’s accelerated approval program in 2000 for use as a single agent in patients with CD33-positive AML who had experienced their first relapse and were 60 years or older. In 2010, Pfizer voluntarily withdrew MYLOTARG after a confirmatory Phase 3 trial (SWOG S0106) did not show a clinical benefit, and the rate of fatalities as a result of treatment-related toxicity was significantly higher in the MYLOTARG arm.

While ODAC discussed MYLOTARG for newly-diagnosed CD33-positive AML, Pfizer is currently seeking approval in the U.S. for MYLOTARG in two indications:

In combination with standard chemotherapy for the treatment of previously untreated de novo CD33-positive AML.
As monotherapy for the treatment of CD33-positive AML patients in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy.
MYLOTARG is commercially available in Japan where it is approved for the treatment of patients with relapsed or refractory CD33-positive AML who are not considered candidates for other cytotoxic chemotherapy.

MYLOTARG originates from a collaboration between Pfizer and Celltech, now UCB. Pfizer has sole responsibility for all manufacturing and clinical development activities for this molecule.