On April 1, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion recommending the grant of a conditional marketing authorization for DARZALEX (daratumumab) in the European Union (Press release, Genmab, APR 1, 2016, View Source [SID:1234510294]). The recommendation is for the use of DARZALEX as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.

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The positive opinion of the CHMP was predominantly based on data from the Phase II study (SIRIUS MMY2002, published in The Lancet in January 2016) of daratumumab in multiple myeloma patients who have received at least three prior lines of therapy including both a PI and an immunomodulatory agent, or who are double refractory to a PI and an immunomodulatory agent.
Additional data from four other studies, including the Phase I/II GEN501 monotherapy study (published in The New England Journal of Medicine in August 2015) support the opinion. In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop, manufacture and commercialize daratumumab.

"We are very pleased to receive the positive opinion from the CHMP for the use of DARZALEX as monotherapy in patients with relapsed and refractory multiple myeloma. The CHMP opinion brings Genmab and its partner Janssen one step closer towards offering a fundamentally new treatment option to patients with multiple myeloma in Europe, and we look forward to the decision of the European Commission," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

A CHMP opinion is one of the final steps in the regulatory process of the European Medicines Agency. The CHMP reviewed DARZALEX under the EMA’s accelerated assessment program. A final decision by the European Commission is anticipated in 60 — 90 days.

In November 2015, DARZALEX was approved by the U.S. FDA under a Breakthrough Therapy Designation and Priority Review 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.

Safety and Efficacy Data from the Phase II MMY2002 (SIRIUS) Study

Results from the pivotal Phase II SIRIUS study showed that treatment with single-agent DARZALEX resulted in an overall response rate (ORR) of 29.2% in patients who had received a median of five prior lines of therapy, including a PI and an immunomodulatory agent. Stringent complete response (sCR) was reported in 2.8% of patients, very good partial response (VGPR) was reported in 9.4% of patients, and partial response (PR) was reported in 17% of patients.1

For responders, the median duration of response was 7.4 months. At baseline, 97% of patients were refractory to their last line of therapy, 95% were refractory to both a PI and an immunomodulatory agent, and 77% were refractory to alkylating agents.1
The warnings and precautions for DARZALEX include infusion-related reactions (IRRs) and interference with serological testing.1 The most commonly occurring adverse reactions (in 20 percent or more of patients in three pooled clinical studies) were IRRs, fatigue, nausea, back pain, anemia, neutropenia (abnormally low levels of neutrophils, a type of white blood cell) and thrombocytopenia (abnormally low levels of platelets in the blood).1

In data from three pooled clinical studies including a total of 156 patients, four percent of patients discontinued treatment due to adverse reactions, none of which were considered drug-related. IRRs were reported in approximately half of all patients treated with DARZALEX, the majority of which (91 percent) occurred during the first infusion. Seven percent of patients had an IRR at more than one infusion. Common (≥5 percent) symptoms of IRRs included nasal congestion, chills, cough, allergic rhinitis, throat irritation, dyspnea, and nausea, and these were mild to moderate in severity.1 Severe IRRs (4 percent), including bronchospasm (1.3 percent), hypertension (1.3 percent), and hypoxia, or decreased oxygen supply to the tissues (0.6 percent), were also reported.1

About multiple myeloma

Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.2 Multiple myeloma is the third most common blood cancer in the U.S., after leukemia and lymphoma.3 Approximately 26,850 new patients were estimated to be diagnosed with multiple myeloma and approximately 11,240 people would die from the disease in the U.S. in 2015.4 Globally, it was estimated that 124,225 people would be diagnosed and 87,084 would die from the disease in 2015.5 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.6 Patients who relapse after treatment with standard therapies, including proteasome inhibitors or immunomodulatory agents, have poor prognoses and few treatment options.7

About DARZALEX (daratumumab)

DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.1 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis,1,8 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,1,8 antibody-dependent cellular phagocytosis9,10 and antibody-dependent cellular cytotoxicity.1,8 In addition, daratumumab therapy results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and subsets of regulatory T cells (Tregs) and B cells (Bregs), all of which express CD38. These reductions in MDSCs, Tregs and Bregs were paralleled by increases in CD4+ and CD8+ T cell numbers in both the peripheral blood and bone marrow.1

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin’s lymphoma.

In the early stages of human papillomavirus (HPV) infection, the viral proteins elicit specific immune responses that can participate to regression of ano-genital lesions. HPV E6 protein for instance can reduce type I interferon (IFN) including IFN-κ that is involved in immune evasion and HPV persistence. To evaluate the role of E2 protein in innate immunity in HPV16-associated cervical lesions, genome-wide expression profiling of human primary keratinocytes (HPK) transduced by HPV16 E2 was investigated using microarrays and innate immunity associated genes were specifically analyzed. The analyses showed that the expression of 779 genes was modulated by HPV16E2 and 92 of them were genes associated with innate immunity. Notably IFN-κ and STING were suppressed in HPK expressing the E2 proteins of HPV16 or HPV18 and the trans-activation amino-terminal domain of E2 was involved in the suppressive effect. The relationship between STING, IFN-κ and interferon stimulated genes (ISGs) in HPK was confirmed by gene silencing and real time PCR. The expression of STING and IFN-κ were further determined in clinical specimens by real time PCR. STING and IFN-κ were down-modulated in HPV positive low grade squamous intraepithelial lesions compared with HPV negative controls. This study demonstrates that E2 proteins of high risk HPV reduce STING and IFN-κ transcription and its downstream target genes that might be an immune evasion mechanism involved in HPV persistence and cervical cancer development.

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Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma (MM) and both, its surface expression as well as its biological significance as key sensor of the unfolded protein response make GRP78 an ideal candidate for immunotherapeutic intervention. The monoclonal antibody PAT-SM6 targets surface (s) GRP78 and leads to disease stabilization when used as single-agent in a clinical trial. In this paper, we evaluated expression of GRP78 in relapsed-refractory disease and explored PAT-SM6 therapy in combination regimens.
GRP78 expression was immunohistochemically analyzed during disease progression and development of drug resistance throughout different stages of MM. Activity of PAT-SM6 was evaluated in combination with anti-MM agents lenalidomide, bortezomib and dexamethasone in vitro. Finally, we report on a MM patient with relapsed and refractory disease treated with PAT-SM6 in combination with bortezomib and lenalidomide.
Although sGRP78 expression was present at all stages, it increased with disease progression and was even stronger elevated in patients with drug-resistant and extramedullary disease. Pre-treatment with dexamethasone as well as dual combination of PAT-SM6/lenalidomide further increased sGRP78 expression and consecutively showed synergistic anti-MM effects with PAT-SM6 in proliferation assays. As proof of concept, a 62-year-old male with triple resistant MM treated with PAT-SM6, bortezomib and lenalidomide experienced partial remission of both intra- and extramedullary lesions.
PAT-SM6 therapy in combination regimens showed efficacy in relapsed refractory MM.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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On April 1, 2016. Medigene AG (MDG1, Frankfurt, Prime Standard), a clinical stage immune-oncology company, reported the treatment start of the first phase II-patient in its dendritic cell (DC) vaccine clinical phase I/II trial in acute myeloid leukaemia (AML) (Press release, MediGene, APR 1, 2016, View Source [SID:1234510295]). This triggers a milestone payment in the amount of approx. 3.2 m EUR to be made by Medigene AG to former contributing shareholders of Medigene Immunotherapies GmbH (formerly: Trianta Immunotherapies GmbH) within the next five months. Medigene intends to settle this payment through the issuance of new shares from authorised capital. The milestone payment was an agreed part of the purchase price in the acquisition of Trianta in January 2014.

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Prof. Dolores J. Schendel, CEO of Medigene AG, comments: "We are glad to announce the start of the clinical phase II trial of our DC vaccines shortly after the successful completion of patient recruitment for the phase I part of this trial and the Data and Safety Monitoring Board’s recommendation to continue clinical development in this project. This demonstrates the steady progress of our clinical programs and the further validation of our immunotherapies."

Study design: Medigene’s Phase I/II trial (NCT02405338) will include 20 AML patients who show complete remission after standard chemotherapy but are not eligible for stem cell transplantation that would reduce the risk of a relapse. Patients will be vaccinated with Medigene’s DC vaccines for 50 weeks with a follow-up period of one year or until progression of the disease. The primary objective is to prove feasibility and safety of active immunotherapy with Medigene’s dendritic cells. Secondary objectives of the study are induction of tumour-specific immune response, control of minimal residual disease (MRD), and clinical response/time to progression (TTP).

About Medigene’s DC vaccines: The platform for the development of antigen-tailored DC vaccines is the most advanced of Medigene’s highly innovative and complementary immunotherapy platforms. Currently Medigene evaluates its DC vaccines in a company-sponsored Phase I/II clinical trial in acute myeloid leukaemia (AML). Further studies utilising Medigene’s DC vaccine technology include two ongoing clinical investigator-initiated trials (IITs), i.e. a clinical Phase I/II trial for the treatment of acute myeloid leukaemia (AML) at Ludwig Maximilians University Hospital Grosshadern, Munich, and a clinical Phase II trial for prostate cancer treatment at Oslo University Hospital. Moreover, compassionate use[1] patients are treated with DC vaccines at the Department of Cellular Therapy at Oslo University Hospital.

Dendritic cells (DCs) are the most potent antigen-presenting cells of our immune system. Their task is to take up, process and present antigens on their cell surface, which enables them to activate antigen-specific T cells for maturation and proliferation. This way T cells can recognise and eliminate antigen-bearing tumour cells. Dendritic cells can also induce natural killer cells (NK cells) to attack tumour cells. The team of Medigene Immunotherapies scientists has developed new, fast and effective methods for generating dendritic cells ex-vivo, which are able to activate both T cells and NK cells. The DC vaccines are developed from autologous (patient-derived) precursor cells, isolated from the patient’s blood, and can be loaded with tumour-specific antigens to treat different types of cancer. Medigene’s DC vaccines are in development for the treatment of minimal residual disease or for the use in combination therapies.

Further audio-visual information about Medigene’s DC vaccines at:
View Source

About acute myeloid leukaemia (AML)

Acute myeloid leukaemia is a malignant disease of the hematopoietic system, affecting mainly adults above 60 years of age. In Germany, about 3,600 incidences are registered annually.

AML is caused by uncontrolled growth of dysfunctional hematopoietic precursor cells in the bone marrow. These cells prevent the generation of normal blood cells, causing a drop in erythrocytes and platelets, for example. Typical symptoms of AML include anaemia, fever, increased risk of infection, and blood coagulation disorder. AML progresses rapidly and may be fatal within a few weeks if untreated.

AML is treated initially with intensive chemotherapy. Another treatment option is allogeneic hematopoietic stem cell transplantation. Unfortunately the majority of patients suffer a relapse. Only about 15 – 20 % of the patients show long-term remission after conventional chemotherapy. Allogeneic hematopoietic stem cell transplantation is the only treatment option that offers a more positive prognosis.

Venetoclax is a selective, first-in-class, Bcl-2 inhibitor that has demonstrated clinical efficacy in several hematological malignancies. Two studies evaluated the relative bioavailability of venetoclax in healthy subjects: 1) a bioequivalence study to compare the bioavailability of the film-coated tablet to that of an earlier uncoated tablet and 2) a food effect study to evaluate the effect of food on venetoclax pharmacokinetics. Both studies were open-label, single-dose, crossover studies. In the bioequivalence study, 15 subjects received a single dose of venetoclax 50 mg under nonfasting conditions in each of two periods; one period used the uncoated tablet and the other used the film-coated tablet. In the food effect study, 24 subjects received a single dose of venetoclax film-coated 100 mg tablet under fasting conditions, after a low-fat breakfast, or after a high-fat breakfast in different periods. The venetoclax film-coated tablet was bioequivalent to the uncoated tablet which indicates that the film coating does not impact the bioavailability. Median Tmax of venetoclax was delayed by about 2 hours when administered with food. Compared to fasting conditions, Cmax and AUC increased by approximately 3.4-fold following a low-fat breakfast. High-fat meals increased Cmax and AUC by approximately 50% relative to low fat meals. The mean terminal half-life was comparable between the high-fat meal and fasting conditions (19.1 hours versus 16.1 hours). Based on these results and the venetoclax exposure-response profile, venetoclax should be administered with food, and without specific recommendations for fat content, to ensure adequate and consistent bioavailability. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.

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