On July 26, 2016 BIND Therapeutics, Inc. (NASDAQ: BIND), a biotechnology company developing targeted and programmable therapeutics called ACCURINS, reported that Pfizer Inc. (NYSE: PFE) prevailed at a Section 363 auction to purchase substantially all of BIND’s assets (Press release, BIND Therapeutics, JUL 26, 2016, View Source [SID1234556287]). The winning bid of $40 million, subject to U.S. Bankruptcy Court approval for which a hearing is scheduled to take place on July 27, 2016, was selected as the highest and best bid. NanoCarrier Co., Ltd. has been selected as the back-up bidder. The Company plans to disclose additional terms of its agreement with Pfizer upon Court approval.

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BIND initiated voluntary Chapter 11 bankruptcy protection on May 1, 2016 and conducted a sale of assets, pursuant to Section 363 of the Bankruptcy Code, during an auction held on July 25 and 26, 2016.

On July 25, 2016 Medigene AG (MDG1, Frankfurt, Prime Standard), a clinical stage immune-oncology company focusing on the development of T cell immuno-therapies for the treatment of cancer, reported the grant of US patent US9,341,617B2 (Press release, MediGene, JUL 25, 2016, View Source [SID:1234514024]). The patent, with an expected life-span until 2030, claims a method for the identification of antigens recognized by CD4+ T cells, including tumor infiltrating CD4+ T cells.

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This patent expands Medigene’s T-cell receptor (TCR) platform technology with an additional fast and efficient method for the direct identification of antigens and respective epitopes recognized by CD4+ tumor infiltrating lymphocytes and opens the way to identify immune relevant patient-specific neoantigens. Rapid definition of epitopes recognized by CD4+ T helper cells for generation of tumor vaccines also becomes potentially possible.

Prof. Dolores Schendel, CEO and CSO of Medigene, explains: "This newly patented method provides the company with a potential additional source for new TCR candidates and also allows us to identify patient-specific neoantigens seen by CD4+ T cells. While CD4+ tumor infiltrating T cells have been known in the past, finding the antigens for which these T cells are specific was very time-consuming and complex. With the covered method we are now able to overcome these problems and it helps us to provide expanded options for adoptive T-cell therapies with transgenic T-cell receptors."

Medigene holds an exclusive license to the patent that was issued to Helmholtz Zentrum München (German Research Center for Environmental Health). Patents within the same patent family have already been granted in Europe, Australia and Canada.

About Medigene’s TCR patent portfolio: Medigene’s IP-portfolio relating to the TCR platform comprises 4 patent families covering methods for the identification of tumor-antigen specific T cell receptors and T cell receptors targeting specific tumor antigens. The 4 patent families in turn comprise 47 granted patents (including validations in Europe) and 14 pending applications. In addition, Medigene is constantly expanding its IP portfolio by filing applications for new methods and newly identified T-cell receptors specific for various tumor-antigens.

About CD4+ T cells in tumor biology: Recent advances in cellular immunotherapy show that cancer cells can be efficiently eliminated by adoptive transfer of modified patient T cells. The main effector functions can be provided by genetically engineered lymphocytes expressing T-cell receptors isolated from tumor antigen-specific cytotoxic CD8+ lymphocytes, which recognize tumor-associated antigens presented on HLA class I molecules. Nevertheless, CD4+ T lymphocytes play a critical role for efficient and sustained cytotoxic CD8+ T cell responses and memory function. Multifunctional CD4+ T cells are essential to activate, control and maintain immune responses. CD4+ T cells recognize antigens presented on HLA class II molecules; thereby HLA class II tumor antigen-positive cells may be efficiently eliminated also by direct CD4+ cytotoxic mechanisms. It was demonstrated that adoptive transfer of tumor antigen-specific CD4+ T cells alone can lead to substantial regression of epithelial tumors (Science. 2014 May 9;344(6184):641-5).

About Medigene’s TCR technology:
The TCR technology aims at arming the patient’s own T cells with tumor-specific T-cell receptors. The receptor-modified T cells are then able to detect and efficiently kill tumor cells. This immunotherapy approach attempts to overcome the patient’s tolerance towards cancer cells and tumor-induced immunosuppression by activating and modifying the patient’s T cells outside the body (ex-vivo). A large number of specific T cells to fight the tumor is thereby made available to patients within a short period of time.

Medigene’s technology for T-cell receptor-modified T cells is one of the company’s highly innovative and complementary immunotherapy platforms for adoptive T-cell therapy. The TCR therapy is designed to treat patients with high tumor loads. Medigene is preparing the clinical development of its first TCR candidates and is developing a library of recombinant T-cell receptors. Moreover, a Good Manufacturing Practice (GMP)-compliant process for their combination with patient-derived T cells is currently being established. Medigene plans to commence its first own clinical TCR trials in 2017 and a second in 2018.

On July 25, 2016 Celgene Corporation (NASDAQ: CELG) and the Lymphoma Study Association (LYSA) reported that the Lymphoma Academic Research Organisation (LYSARC) reported initial data from a phase III, randomized, double-blind, international clinical study (REMARC) (Press release, Celgene, JUL 25, 2016, View Source [SID:1234514026]). This investigational study evaluated maintenance therapy with REVLIMID (lenalidomide) compared with placebo in diffuse large B-cell lymphoma (DLBCL) patients responding to first-line rituximab plus CHOP chemotherapy (R-CHOP) induction therapy. LYSARC sponsored the study under a Clinical Trial Agreement with Celgene.

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REMARC achieved the primary endpoint of a statistically significant improvement in progression-free survival for patients receiving REVLIMID. The interim analysis of overall survival, a key secondary endpoint, showed no benefit in the REVLIMID arm. Based upon these interim results, Celgene does not currently plan to seek approval for this indication.

"We thank the patients and their families for participating in the REMARC trial and look forward to presenting these important data at a future hematology conference," said Bertrand Coiffier, Professor of Hematology, Hospices de Lyon and University Claude Bernard Lyon 1 and Principal Investigator, REMARC.

"We are continuing to partner with LYSA to complete the analyses of the REMARC study," said Michael Pehl, President Hematology and Oncology of Celgene. "We remain committed to finishing the four ongoing phase III trials evaluating REVLIMID and are confident about its potential as a treatment option across different settings in lymphoma."

A Broad Phase III Program in NHL Underway; Data from Additional Trials Expected in 2017

The REMARC study is part of a broad research program at Celgene focused on multiple areas of non-Hodgkin lymphoma. In addition to the REMARC study, REVLIMID is also being evaluated in:

RELEVANCE, a combination with rituximab in previously untreated follicular lymphoma;
AUGMENT, a combination with rituximab in relapsed/refractory follicular and marginal zone lymphoma;
MAGNIFY, a combination with rituximab in relapsed/refractory follicular, marginal zone and mantle cell lymphoma; and,
ROBUST, a combination with R-CHOP in previously untreated ABC-subtype DLBCL.
Data from RELEVANCE and AUGMENT are expected in the first and second half of 2017, respectively. Beyond REVLIMID, Celgene is also exploring multiple clinical candidates in non-Hodgkin lymphomas and T-cell lymphomas.

REVLIMID is not approved for use in DLBCL.

About REMARC

REMARC is an international, multicentre, randomized, double-blind, placebo-controlled phase III study designed to explore the effect of maintenance therapy with REVLIMID (lenalidomide) versus placebo on progression-free survival (PFS) in 650 patients treated with R-CHOP responding to induction therapy. Patients in REMARC had received at least 6 and up to 8 cycles of the R-CHOP 14 or R-CHOP 21 regimen or 6 R-CHOP-14 or -21 completed by 2 cycles of rituximab alone in accordance to local preferences. Evaluation of the response to R-CHOP was in accordance with Revised Response Criteria for Malignant Lymphoma (2007). The primary endpoint of the study was progression-free survival. The secondary endpoints of the study included overall survival, event-free survival, response at the end of maintenance, improvement in response and safety.

About REVLIMID

In the United States, REVLIMID is approved in combination with dexamethasone for the treatment of patients with multiple myeloma. REVLIMID is also approved in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy in nearly 70 countries, encompassing Europe, the Americas, the Middle East and Asia, and in combination with dexamethasone for the treatment of patients whose disease has progressed after one therapy in Australia and New Zealand.

REVLIMID is also approved in the United States, Canada, Switzerland, Australia, New Zealand and several Latin American countries, as well as Malaysia and Israel, for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities and in Europe for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.

In addition, REVLIMID is approved in the United States for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

U.S. Regulatory Information for REVLIMID

REVLIMID (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM)

REVLIMID is indicated for the treatment of patients with transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities

REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib

REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Important Safety Information
WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity
Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS program (formerly known as the "RevAssist" program).

Information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)
REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.

Venous and Arterial Thromboembolism
REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

CONTRAINDICATIONS

Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus

Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: See Boxed WARNINGS

Females of Reproductive Potential: See Boxed WARNINGS
Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm
Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID
REVLIMID REMS Program: See Boxed WARNINGS: Prescribers and pharmacies must be certified with the REVLIMID REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive REVLIMID. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements

Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. MM: Patients taking REVLIMID/dex should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter. MDS: Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or dose reduction. Please see the Black Box WARNINGS for further information. MCL: Patients taking REVLIMID for MCL should have their CBCs monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction

Venous and Arterial Thromboembolism: See Boxed WARNINGS: Venous thromboembolic events (DVT and PE) and arterial thromboses (MI and CVA) are increased in patients treated with REVLIMID. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended and regimen is based on patients underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision

Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials

Second Primary Malignancies (SPM): In clinical trials in patients with MM receiving REVLIMID, an increase of invasive SPM notably AML and MDS have been observed. Monitor patients for the development of SPMs. Take into account both the potential benefit of REVLIMID and risk of SPMs when considering treatment

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID/dex. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered

Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose; risk-benefit of treatment should be evaluated in patients with lactose intolerance

Tumor Lysis Syndrome (TLS): Fatal instances of TLS have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken

Tumor Flare Reaction (TFR): TFR has occurred during investigational use of lenalidomide for CLL and lymphoma. Monitoring and evaluation of TFR is recommended in patients with MCL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with REVLIMID until TFR resolves to ≤ Grade 1. REVLIMID may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment ( > 4 cycles) with REVLIMID has been reported. Consider early referral to transplant center to optimize timing of the stem cell collection

ADVERSE REACTIONS

Multiple Myeloma

In newly diagnosed: The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or RD18
The most common adverse reactions reported in ≥20% (Arm Rd Continuous): diarrhea (46%), anemia (44%), neutropenia (35%), fatigue (33%), back pain (32%), asthenia (28%), insomnia (28%), rash, (26%), decreased appetite (23%), cough (23%), dyspnea (22%), pyrexia (21%), abdominal pain (21%), muscle spasms (20%), and thrombocytopenia (20%)
After at least one prior therapy the most common adverse reactions reported in ≥20% (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), and weight decreased (20% vs 15%)
Myelodysplastic Syndromes

Grade 3 and 4 adverse events reported in ≥ 5% of patients with del 5q MDS were neutropenia (53%), thrombocytopenia (50%), pneumonia (7%), rash (7%), anemia (6%), leukopenia (5%), fatigue (5%), dyspnea (5%), and back pain (5%)
Adverse events reported in ≥15% of del 5q MDS patients (REVLIMID): thrombocytopenia (61.5%), neutropenia (58.8%), diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral edema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%), asthenia (15%), upper respiratory tract infection (15%)
Mantle Cell Lymphoma

Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%)
Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%)
DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels is recommended due to increased Cmax and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as erythropoietin stimulating agents or estrogen containing therapies may have an increased risk of thrombosis. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin

NURSING MOTHERS

Discontinue drug or nursing taking into consideration the importance of the drug to the mother

PEDIATRIC USE

Safety and effectiveness in patients below the age of 18 have not been established

RENAL IMPAIRMENT

REVLIMID is primarily excreted unchanged by the kidneys; adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis

Please see full Prescribing Information, including Boxed WARNINGS.

About LYSARC

The Lymphoma Academic Research Organisation (LYSARC), located in Lyon, France, is an academic clinical research organization running international clinical lymphoma trials in affiliation with the LYSA and in collaboration with other renowned, international cooperative groups. For more information, please visit www.lysarc.org.

About LYSA

The Lymphoma Study Association (LYSA), is a French association leader in international clinical and translational research in lymphoma, with a network of 130 centers in France, Switzerland, Portugal and Belgium. For more information, please visit www.lysa-lymphoma.org

On July 25, 2016 Janssen Research & Development, LLC reported that the U.S. Food and Drug Administration (FDA) has granted a Breakthrough Therapy Designation to the immunotherapy daratumumab (DARZALEX) in combination with lenalidomide (an immunomodulatory agent) and dexamethasone, or bortezomib (a proteasome inhibitor [PI]) and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy (Press release, Johnson & Johnson, JUL 25, 2016, View Source [SID:1234514044]). This marks the second time daratumumab has received a Breakthrough Therapy Designation, which is intended to expedite the development and review timelines of potential new medicines to treat serious or life-threatening diseases, where preliminary clinical evidence shows that the medicine may provide substantial improvement over existing therapies. 1 Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow.2,3

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"Despite tremendous progress in the past 15 years, multiple myeloma remains a highly complex and difficult disease to treat, with most patients relapsing or becoming resistant to therapy," said MMY3003 (POLLUX) lead study author Meletios A. Dimopoulos, M.D., Department of Clinical Therapeutics, National and Kapodistrian 2 University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece. "Daratumumab has already shown pronounced activity as a monotherapy in heavily pre-treated patients. This designation underscores the potential of daratumumab in combination with either a proteasome inhibitor or an immunomodulatory agent to provide much-needed benefit to patients with at least one prior therapy."

Breakthrough Therapy Designation was granted to daratumumab based on data from two Phase 3 studies:

The MMY3004 (CASTOR) clinical trial evaluating daratumumab in combination with bortezomib and dexamethasone, compared to bortezomib and dexamethasone alone, in patients with multiple myeloma who received at least one prior therapy. Overall, the daratumumab combination therapy demonstrated a reduction in the risk of disease progression or death.
o These results were presented at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in June 2016. More information can be found at www.ClinicalTrials.gov (NCT02136134).

The MMY3003 (POLLUX) clinical trial evaluating daratumumab in combination with lenalidomide and dexamethasone, compared to lenalidomide and dexamethasone alone, in patients with multiple myeloma who received at least one prior therapy. Overall, the addition of daratumumab reduced the risk of disease progression or death in these patients.
o These results were presented at the 21st Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in June 2016. More information can be found at www.ClinicalTrials.gov (NCT02076009).

"We are pleased that the FDA has granted a second Breakthrough Therapy Designation to daratumumab. This is an important recognition of the transformative potential of daratumumab and its possible benefit as a backbone therapy in combination with two of the most widely used regimens for multiple myeloma," said Craig L. Tendler, M.D., Vice President, Late-Stage Development and Global Medical Affairs for Oncology, Hematology and Supportive Care, Janssen Research & Development, LLC. "We look forward to working closely with the FDA throughout the review process and remain committed to exploring the full clinical benefit of this promising compound for multiple myeloma patients who are eagerly awaiting new treatment options."

In November 2015, daratumumab (DARZALEX) was approved by the FDA for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.4

In May 2013, daratumumab received Breakthrough Therapy Designation from the FDA for this indication. 3 In May 2016, the European Commission (EC) granted conditional approval to DARZALEX for monotherapy of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.

About DARZALEX (daratumumab)

DARZALEX (daratumumab) injection for intravenous use is the first CD38-directed monoclonal antibody (mAb) approved anywhere in the world.4 CD38 is a surface protein that is highly expressed across multiple myeloma cells, regardless of disease stage. 5 Daratumumab is believed to induce tumor cell death through multiple immunemediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), as well as through apoptosis, in which a series of molecular steps in a cell lead to its death.4 Daratumumab is also believed to induce tumor cell death through immunomodulatory effects, according to a study recently presented at the 57th Annual Meeting and Exposition of the American Society of Hematology (ASH) (Free ASH Whitepaper).6 DARZALEX is being evaluated in a comprehensive clinical development program that includes five Phase 3 studies across a range of treatment settings in multiple myeloma, such as in frontline and relapsed settings. Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases in which CD38 is expressed, such as smoldering myeloma, non-Hodgkin’s lymphoma and a solid tumor indication. DARZALEX was the first mAb to receive regulatory approval to treat relapsed or refractory multiple myeloma.4

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialize DARZALEX. DARZALEX is commercialized in the U.S. by Janssen Biotech, Inc. For more information, visit www.DARZALEX.com.

About Multiple Myeloma

Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow.7,8 Refractory cancer occurs when a patient’s disease is resistant to treatment or in the case of multiple myeloma, patients progress within 60 days of their last therapy.9,10 Relapsed cancer means the disease has returned after a period of initial, partial or complete remission.7,11 Accounting for approximately one percent of all cancers and 15 percent to 20 percent of haematologic malignancies worldwide, multiple myeloma is designated as an orphan disease in both the U.S. and Europe. 11 Globally, it is estimated that 124,225 people were diagnosed, and 87,084 died from the disease in 2015. 12,13 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone fracture or pain, low red blood counts, fatigue, calcium elevation, kidney problems or infections.14 Patients who relapse after treatment with standard therapies (including PIs or immunomodulatory agents) typically have poor prognoses and few remaining options.3

DARZALEX (daratumumab) Important Safety Information – Professional 4

CONTRAINDICATIONS – None

WARNINGS AND PRECAUTIONS
Infusion Reactions – DARZALEX can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, and hypertension. Signs and symptoms may include respiratory symptoms, such as cough, wheezing, larynx and throat tightness and irritation, laryngeal edema, pulmonary edema, nasal congestion, and allergic rhinitis. Less common symptoms were hypotension, headache, rash, urticaria, pruritus, nausea, vomiting, and chills.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients the first and second day after all infusions. Patients with a history of obstructive pulmonary disorders may require additional postinfusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with obstructive pulmonary disorders.

Interference with Serological Testing – Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX.

Interference with Determination of Complete Response – Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Adverse Reactions – The most frequently reported adverse reactions (incidence ≥20%) were: infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). 5 Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%).

DRUG INTERACTIONS – No drug interaction studies have been performed

On July 25, 2016 KaloBios Pharmaceuticals, Inc. (OTC:KBIO), a biopharmaceutical company focused on advancing medicines for patients with neglected and rare diseases, reported that the first patient has been dosed in its open-label, multi-center Phase 1 clinical trial with lenzilumab (formerly KB003) focused on patients with previously-treated Chronic Myelomonocytic Leukemia (CMML) (Press release, KaloBios, JUL 25, 2016, View Source [SID:1234514144]).

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This multi-center Phase 1 dose escalation trial is being conducted to evaluate the safety, maximum tolerated dose, and preliminary activity of single-agent lenzilumab in subjects with CMML who are relapsed/refractory to, and/or intolerant to, standard-of-care treatments.

"The new KaloBios is now in action mode, and the first dosing of a patient in the lenzilumab study highlights our pivot to swift execution in advancing our pipeline assets," said Cameron Durrant, MD, KaloBios chairman and CEO. "CMML is a rare and devastating disease for which there are limited effective treatment options currently available. We anticipate this trial will demonstrate lenzilumab’s potential to help patients who need new treatment options and support its continued clinical advancement."

The study will enroll up to 18 patients and is designed to identify the maximum tolerated dose, or recommended Phase 2 dose, of lenzilumab in subjects with previously-treated CMML. It will also assess preliminary efficacy of single-agent lenzilumab and to provide additional data on pharmacokinetics, pharmacodynamics and safety.

"The first patient to receive treatment in this study also signifies the first of many important clinical milestones ahead for KaloBios, as we seek to tackle neglected and rare diseases through innovative and responsible business models," added Dr. Durrant.

About Lenzilumab

Lenzilumab is a monoclonal antibody that targets and is an antagonist of soluble Granulocyte Macrophage – Colony Stimulating Factor (GM-CSF), a cytokine suggested to be central to the inflammation and activation of certain immune cells. Lenzilumab has been studied for its ability to limit hypersensitivity to GM-CSF signaling, which appears to be a key feature to many CMML patients and its inhibition may affect the growth of leukemic cells in patients. Lenzilumab has been tested in more than 90 subjects in previous clinical trials in rheumatoid arthritis, asthma and healthy volunteers, and was found to be well tolerated. Data also suggest lenzilumab may have the potential to treat other diseases, including juvenile myelomonocytic leukemia (JMML).

About CMML

CMML is a rare and aggressive cancer of the blood with approximately 1,500-3,000 new cases per year in the United States. The cancer interferes with normal blood cell production, including red blood cells, white blood cells and platelets. CMML patients have shortened life expectancies, with a median survival rate of one to two years, and approximately 15-30 percent of patients will go on to develop acute leukemia.