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:
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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.

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.

On April 1, 2016 BioWa, Inc. ("BioWa") reported that it was relocating its office from La Jolla, California to Princeton, New Jersey, and appointment of Mr. Takeshi Masuda, as the President and CEO for the next stage of corporate development (Press release, Kyowa Hakko Kirin, APR 1, 2016, View Source [SID:1234510289]).

Mr. Masuda has also served as President of Kyowa Kirin USA Holdings, Inc. the holding company of Kyowa Hakko Kirin’s US pharmaceutical subsidiaries.

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BioWa develops partnerships with pharmaceutical companies and biotechs through the licensing of proprietary therapeutic antibody technologies POTELLIGENT and COMPLEGENT. These technologies were developed by Kyowa Hakko Kirin, Co. Ltd. and BioWa will be continuing a role as the exclusive worldwide licensor of those technologies after relocation to Princeton.

On April 1, 2016 Can-Fite BioPharma Ltd. (NYSE MKT: CANF) (TASE:CFBI), a biotechnology company with a pipeline of proprietary small molecule drugs being developed to treat inflammatory diseases, cancer and sexual dysfunction, reported it has filed its 2015 Annual Report on Form 20-F with the U.S. Securities and Exchange Commission (Filing, Annual, Can-Fite BioPharma, 2015, APR 1, 2016, View Source [SID:1234510288]).

Clinical Development Program and Corporate Highlights Include:

● CF101 – Preparing Phase III Trials in Rheumatoid Arthritis & Psoriasis Scheduled to Commence in 2016

Can-Fite completed its Phase III trial protocol and Registration Plan for CF101 in the treatment of rheumatoid arthritis and submitted it to the European Medicines Agency (EMA) in March 2016. The Company anticipates commencing the trial in the second or third quarter of 2016.

The Phase III trial protocol for CF101 in the treatment of psoriasis is nearing completion, and is planned to be filed with the EMA in the first half of 2016, with study initiation expected in the fourth quarter of 2016.

● CF102 – Conducting Phase II Trial in Liver Cancer & Plans to Commence Phase II Trial in NASH

Can-Fite continues to enroll and dose patients in its global Phase II liver cancer study in the U.S., Europe, and Israel. Completion of enrollment with approximately 78 patients is expected in the second half of 2016. In 2015, the U.S. Food and Drug Administration (FDA) granted Fast Track Designation to CF102 as a second line treatment for hepatocellular carcinoma (HCC) in patients who have previously received Nexavar (sorafenib). HCC is the most common form of liver cancer. CF102 has Orphan Drug Designation in the U.S. for HCC and in 2015 also received Orphan Drug Designation from the EMA for the indication of HCC.

Following compelling preclinical data reported in 2015 on CF102’s efficacy in the treatment of non-alcoholic steatohepatitis (NASH), Can-Fite is preparing to file its Phase II protocol with institutional review boards (IRBs) in the second quarter of 2016. This new indication for CF102 addresses a market estimated to reach $35-$40 billion by 2025 according to Deutsche Bank.

● CF602 – Preparing to Submit IND to FDA for Treatment of Sexual Dysfunction

Can-Fite is currently conducting further preclinical work for CF602 in the treatment of sexual dysfunction in preparation to submit an investigational new drug (IND) application to the FDA in the fourth quarter of 2016. In 2015, Can-Fite reported new findings showing CF602 demonstrated effects on erectile dysfunction superior to that of Viagra in animal studies.

● OphthaliX – Phase II Results for CF101 in Treatment of Glaucoma Expected in Q2 2016

In 2015, Can-Fite’s subsidiary OphthaliX completed patient enrollment in its Phase II trial for CF101 in the treatment glaucoma and related syndromes of ocular hypertension. The Company expects to report data from this study in the second quarter of 2016.

"We believe our portfolio of small molecule drug candidates has strong potential to address unmet needs in today’s treatment markets. Having been tested in over 1,000 patients to date, our drugs have proven safe and shown efficacy in numerous clinical trials," stated Can-Fite CEO Dr. Pnina Fishman. "We are continuing to conduct a very active clinical program designed to move several of these drugs towards regulatory approvals."

Revenues for the twelve months ended December 31, 2015 were NIS 0.64 million ($0.16 million). We did not record any revenues during the year ended December 31, 2014. The increase in revenue was due to the recognition of a portion of the NIS 5.14 million ($1.32 million) upfront payment received in March 2015 under the distribution agreement with Cipher Pharmaceuticals.

Research and development expenses for the twelve months ended December 31, 2015 were NIS 15.05 million (U.S. $3.86 million) compared with NIS 16.2 million (U.S. $4.15 million) for the same period in 2014. Research and development expenses for 2015 comprised primarily of expenses associated with the Phase II study for CF102 as well as expenses for ongoing studies of CF101. The decrease is primarily due to the completion of the Phase II/III psoriasis study during the first quarter of 2015 and a decrease in the scope of the non-clinical expenses during 2015 as compared to the parallel period in 2014.

General and administrative expenses were NIS 10.63 million (U.S. $2.72 million) for the twelve months ended December 31, 2015 compared to NIS 11.57 million (U.S. $2.97 million) for the same period in 2014. The decrease is primarily due to a reduction in salary and investor and public relations expenses.

Financial income, net for the twelve months ended December 31, 2015 aggregated NIS 5.29 million (U.S. $1.36 million) compared to financial income, net of NIS 3.27 million (U.S. $0.84 million) for the same period in 2014. The increase in financial income, net in 2015 was mainly due to a decrease in the fair value of warrants that are accounted as financial liability.

Can-Fite’s net loss for the twelve months ended December 31, 2015 was NIS 19.77 million (U.S. $5.07 million) compared with a net loss of NIS 24.52 million (U.S. $6.28 million) for the same period in 2014. The decrease in net loss for 2015 was primarily attributable to decreases in operating expenses and an increase in financial income, net.

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As of December 31, 2015, Can-Fite had cash and cash equivalents of NIS 66.03 million (U.S. $16.92 million) as compared to NIS 36.09 million (U.S. $9.25 million) at December 31, 2014. The increase in cash during the twelve months ended December 31, 2015 is due to NIS 48.33 million (U.S. $12.39 million) raised from registered direct offerings in September and October 2015 and NIS 5.14 million (U.S. $1.32 million) received from Cipher Pharmaceuticals as upfront payment for entering into the distribution agreement with Cipher offset by operating expenses.

For the convenience of the reader, the reported NIS amounts have been translated into U.S. dollars, at the representative rate of exchange on December 31, 2015 (U.S. $ 1 = NIS 3.902).

The Company’s consolidated financial results for the twelve months ended December 31, 2015 are presented in accordance with International Financial Reporting Standards.

The 2015 Annual Report can be found on the Company’s website at www.canfite.com as well as on the SEC website at www.sec.gov. In addition, security holders may request a hard copy of the Annual Report, which includes the Company’s complete audited financial statements, free of charge. Requests can be made by contacting Can-Fite Investor Relations at 10 Bareket Street, Kiryat Matalon, Petah-Tikva 4951778, Israel or by phone at +972-3-9241114.

Endocrine resistance is a major obstacle to optimal treatment effect in breast cancer. Some genetic markers have been proposed to predict response to aromatase inhibitors (AIs) but the data is insufficient. The aim of the study was to find new genetic treatment predictive markers of AIs.
The ongoing population-based BC-blood study in Lund, Sweden includes women with primary breast cancer. This paper is based on AI-treated patients with estrogen receptor positive tumors who underwent breast cancer surgery in 2002-2008. First, an exploratory analysis of 1931 SNPs in 227 genes involved in absorption, distribution, metabolism, and elimination of multiple medications, using DMET chips, was conducted in a subset of the cohort with last follow-up in December 31(st) 2011 (13 cases, 11 controls). Second, selected SNPs from the first analysis were re-analyzed concerning risk for early breast cancer events in the extended cohort of 201 AI-treated with last follow-up in June 30(th) 2014. Clinical data were obtained from medical records and population registries.
Only CYP1A2 rs762551 C-allele was significantly associated with increased risk for early events in the 24 patients (P = 0.0007) and in the extended cohort, adjusted Hazard ratio (HR) 2.22 (95 % CI 1.03-4.80). However, the main prognostic impact was found within five years, adjusted HR 7.88 (95 % CI 2.13-29.19). The impact of the CYP1A2 rs762551 C-allele was modified by a functional polymorphism in the regulator gene AhR Arg554Lys (G > A). Compared to patients who were homozygous for the major allele in both genes (CYP1A2 A/A and AhR G/G), a 9-fold risk for early events was found in patients who had at least one minor allele in both genes, adjusted HR 8.95 (95 % CI 2.55-31.35), whereas patients with at least one minor allele in either but not both genes had a 3-fold risk for early events, adjusted HR 2.81 (95 % CI 1.07-7.33). The impact of CYP1A2 rs762551 C-allele was also modified by the CYP19A1 rs4646 C/C, adjusted HR 3.39 (95 % CI 1.60-7.16) for this combination. This association was strongest within the first five years, adjusted HR 10.42 (95 % CI 3.45-31.51).
CYP1A2 rs762551 was identified as a new potential predictive marker for early breast cancer events in AI-treated breast cancer patients. Moreover, combined genotypes of CYP1A2 rs762551 and CYP19A1 rs4646 or AhR Arg554Lys could further improve prediction of early AI-treatment response. If confirmed, these results may provide a way to more personalized medicine.

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