On August 25, 2016 Sunesis Pharmaceuticals, Inc. (Nasdaq:SNSS) reported the publication of an article detailing the molecular and pharmacologic properties of vosaroxin as a new therapeutic for acute myeloid leukemia (AML) in the journal Drugs (Press release, Sunesis, AUG 25, 2016, View Source [SID:1234514730]). The article, titled "Molecular and Pharmacologic Properties of the Anticancer Quinolone Derivative Vosaroxin: A New Therapeutic for Acute Myeloid Leukemia," is available online and will appear in the September 2016 print issue of Drugs.

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The authors describe how the unique chemical and pharmacologic characteristics of vosaroxin, the first quinolone-based topoisomerase II inhibitor studied in clinical trials in cancer, may contribute to the efficacy and safety profile observed in Sunesis’ Phase 3 VALOR trial, a randomized, double-blind, placebo-controlled trial of vosaroxin and cytarabine in patients with first relapsed or refractory AML. Vosaroxin is a DNA intercalating topoisomerase II inhibitor that causes the induction of apoptosis via double-strand DNA breaks, yet is chemically distinct from other topoisomerase inhibitors with its stable quinolone-based core. Due to the stability of this core, vosaroxin is not associated with significant formation of toxic metabolites, free radicals, or reactive oxygen species, which are associated with off-target organ damage and cardiotoxicity. Furthermore, vosaroxin evades two common mechanisms of drug resistance, as it is not a substrate for the P-glycoprotein efflux pump and its activity is maintained in cells with p53 deletion.

In the pivotal Phase 3 VALOR trial, a 2.1-month improvement in median OS among patients ≥ 60 years old was demonstrated, without an increase in early mortality, as compared to the control arm. Common side effects of vosaroxin included gastrointestinal effects, myelosuppression, and infection. Vosaroxin also demonstrates potent in vitro antitumor activity in various tumor types, including those resistant to other topoisomerase II inhibitors.

Vosaroxin is currently being tested in several investigator-sponsored studies, both as a single-agent and in combination with other therapies, for the treatment of AML and myelodysplastic syndromes. A Marketing Authorization Application for vosaroxin as a treatment for AML in Europe is currently under review by the European Medicines Agency.

"The chemical and pharmacologic characteristics of vosaroxin, including its chemically stable quinolone core, low off-target organ damage and ability to overcome common resistance factors, highlight its potential as a new and differentiated treatment option for certain cancers," stated Dr. Stephen A. Strickland, M.D., MSCI, Clinical Director of Acute Leukemia, Division of Hematology/Oncology at the Vanderbilt-Ingram Cancer Center, Assistant Professor of Medicine, Vanderbilt University Department of Medicine, and a lead author of the publication. "In particular, vosaroxin may be an effective therapeutic alternative for older AML patients, those with treatment-resistant disease, and those who have exceeded safe thresholds for anthracyclines or are at high risk for treatment-related cardiac damage. Overall, I believe vosaroxin represents a much needed treatment for patients with relapsed or refractory AML."

"Publication of this profile on vosaroxin in Drugs supports our goal of establishing vosaroxin as a meaningful advancement in the standard of care for patients with AML," said Daniel Swisher, Chief Executive Officer of Sunesis. "As we continue through the process for regulatory approval of vosaroxin in Europe, we also look forward to expanding the body of supportive data behind this therapeutic candidate as we advance several ongoing and planned investigator- or company-sponsored clinical studies."

About QINPREZO (vosaroxin)

QINPREZO (vosaroxin) is an anti-cancer quinolone derivative (AQD), a class of compounds that has not been used previously for the treatment of cancer. Preclinical data demonstrate that vosaroxin both intercalates DNA and inhibits topoisomerase II, resulting in replication-dependent, site-selective DNA damage, G2 arrest and apoptosis. Both the U.S. Food and Drug Administration (FDA) and European Commission have granted orphan drug designation to vosaroxin for the treatment of AML. Additionally, vosaroxin has been granted fast track designation by the FDA for the potential treatment of relapsed or refractory AML in combination with cytarabine. Vosaroxin is an investigational drug that has not been approved for use in any jurisdiction.

Vosaroxin’s Marketing Authorization Application for relapsed refractory AML is currently under review by the European Medicines Agency, and a regulatory decision regarding approval is expected in 2017.

The trademark name QINPREZO is conditionally accepted by the FDA and the EMA as the proprietary name for the vosaroxin drug product candidate.

On August 25, 2016 Mylan N.V. (NASDAQ, TASE: MYL) and Biocon Ltd. (BSE code: 532523, NSE: BIOCON) reported that the European Medicines Agency (EMA) has accepted for review Mylan’s Marketing Authorization Application (MAA) for a proposed biosimilar Trastuzumab, which is used to treat certain HER2-positive breast and gastric cancers (Press release, Mylan, AUG 25, 2016, View Source [SID:1234514729]). This is the second biosimilar submission developed by the partnership that has been accepted for review in Europe. Last month, Mylan’s MAA for the proposed biosimilar Pegfilgrastim was accepted for review by EMA.

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Mylan
Mylan and Biocon, which have co-developed this proposed biosimilar, anticipate that this may be the first MAA for a Trastuzumab biosimilar accepted by the EMA for review.

This filing includes analytical, functional and pre-clinical data, as well as results from the pharmacokinetics (PK) and confirmatory efficacy/safety global clinical trials for Trastuzumab. The PK study had demonstrated measured bioequivalence of Mylan’s and Biocon’s proposed Trastuzumab biosimilar relative to that of the reference drug. The second study, the ‘HERITAGE Study’, evaluated the efficacy, safety and immunogenicity of the proposed biosimilar Trastuzumab in comparison to branded Trastuzumab.
Mylan President Rajiv Malik commented: "The acceptance of our regulatory submission of our proposed biosimilar Trastuzumab in Europe is another example of the strong progress we continue to make across our broad biosimilars portfolio. Following our successful commercialization in India and emerging markets, we look forward to our pending launch in Europe. Europe represents a key market for more affordable versions of these important products, as governments across the region strive to reduce healthcare costs. We look forward to continuing to work to bring this product to patients upon approval."

Arun Chandavarkar, CEO and Joint Managing Director, Biocon, said: "The regulatory submission for proposed biosimilar Trastuzumab in Europe takes us a step closer towards enabling affordable access to this critical biologic therapy for the treatment of HER2-positive breast cancer. We remain committed to bring a diversified portfolio of high-quality, life-enhancing biosimilars to patients globally."

At the annual American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) event held in June this year, 24 week data for the ‘HERITAGE’ study was presented. The results of the 48 week extension data of the ‘HERITAGE’ study are expected to be presented at the upcoming European Society for Medical Oncology Congress (ESMO) (Free ESMO Whitepaper) in October.

About Biocon and Mylan Partnership
Biocon and Mylan are exclusive partners on a broad portfolio of biosimilars and insulin analogs. The proposed biosimilar Trastuzumab is one of the six biologic products co-developed by Mylan and Biocon for the global marketplace. Mylan has exclusive commercialization rights for the proposed biosimilar Trastuzumab in the U.S., Canada, Japan, Australia, New Zealand, the European Union and European Free Trade Association countries. Biocon has co-exclusive commercialization rights with Mylan for the product in the rest of the world.

About HER2-Positive Breast Cancer and Trastuzumab
Worldwide, nearly 2 million women are diagnosed with breast cancer each year, making it the second most common cancer in the world. HER2-positive breast cancer is an aggressive form of breast cancer that tests positive for the human epidermal growth factor receptor 2 (HER2), which promotes cancer cell growth. Approximately 20% to 30% of primary breast cancers are HER2-positive. Trastuzumab is indicated for the treatment of certain HER2-positive early stage and metastatic breast cancer as well as HER2-positive metastatic gastric cancer.

About the Heritage Study
The Phase III study, HERITAGE, is a double-blind, randomized clinical trial designed to evaluate comparative efficacy and safety of the proposed trastuzumab biosimilar, MYL-1401O, versus branded trastuzumab. Eligible patients had centrally confirmed, measurable HER2-positive metastatic breast cancer without prior chemotherapy or trastuzumab for metastatic disease. Patients were randomized to receive either MYL-1401O or branded trastuzumab with docetaxel or paclitaxel for a minimum of eight cycles. Trastuzumab was continued until progression. The primary endpoint is overall response at week 24 by blinded central evaluation using RECIST 1.1. Secondary endpoints include progression free survival, overall survival, and safety. A sample size of 456 patients was calculated to demonstrate equivalence in overall response at week 24 for MYL-1401O versus branded trastuzumab, defined as a 90% confidence interval for the ratio of best overall response rate within the equivalence margin (0.81, 1.24). This study successfully met the predefined equivalence criteria. The response rates at 24 weeks were 69.6% with MYL-1401O combined with taxane chemotherapy versus 64% with branded trastuzumab combined with taxane chemotherapy. The incidence of adverse events was similar in the patients who received MYL-1401O and those who received reference trastuzumab.

About Biosimilars
A biosimilar medicine is a biological medicine that is developed to be similar to an existing biological medicine and has demonstrated no clinically meaningful differences in safety, purity, and potency compared to that of the reference biologic. A biosimilar product and its reference biologic product are expected to have the same safety and efficacy profile and are generally used to treat the same conditions. Biosimilars may offer a less-costly alternative to existing biological medicinal products that have lost their exclusivity rights.

On August 25, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported The New England Journal of Medicine has published data from the Phase III CASTOR (MMY3004) study of daratumumab (Press release, Genmab, AUG 25, 2016, View Source [SID:1234514714]). The CASTOR data were presented at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper). Daratumumab was granted a Breakthrough Therapy Designation (BTD) from the U.S. Food and Drug Administration (FDA) based on these data in July 2016.

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The Phase III CASTOR study included 498 patients who had relapsed or refractory multiple myeloma. Patients were randomized to receive either daratumumab combined with subcutaneous bortezomib (a type of chemotherapy, called a proteasome inhibitor) and dexamethasone (a corticosteroid), or bortezomib and dexamethasone alone. The study met the primary endpoint of improving progression free survival (PFS); Hazard Ratio (HR) = 0.39, p<0.001. The median PFS for patients treated with daratumumab has not been reached, compared to median PFS of 7.2 months for patients who did not receive daratumumab. The overall response rate was 82.9% for patients treated with daratumumab versus an overall response rate of 63.2% in the group that did not receive daratumumab. The rate of very good partial response or better was also higher for the group treated with daratumumab (59.2% vs 29.1%). The most common grade 3 or 4 adverse events in patients treated with daratumumab in combination with bortezomib and dexamethasone compared to those who only received bortezomib and dexamethasone were thrombocytopenia (45.3% vs 32.9%), anemia (14.4% vs 16.0%) and neutropenia (12.8% vs 4.2%). Daratumumab-associated infusion-related reactions were reported in 45.3% of patients, were mostly grade 1/2, and occurred predominantly during the first infusion. This is consistent with the reported safety profile of daratumumab monotherapy and background bortezomib/dexamethasone therapy.

"We are pleased that the positive data from the Phase III CASTOR study of daratumumab, which was presented earlier this year at the ASCO (Free ASCO Whitepaper) and EHA (Free EHA Whitepaper) meetings, has now been published in the prestigious New England Journal of Medicine," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab. "The data from this study formed part of the basis of this month’s submission of the supplemental Biologics License Application to the U.S. Food and Drug Administration and the submission of the variation to the Marketing Authorization to the European Medicines Agency."

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.1 Multiple myeloma is the third most common blood cancer in the U.S., after leukemia and lymphoma.2 Approximately 30,330 new patients are expected to be diagnosed with multiple myeloma and approximately 12,650 people are expected to die from the disease in the U.S. in 2016.3 Globally, it was estimated that 124,225 people would be diagnosed and 87,084 would die from the disease in 2015.4 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.5 Patients who relapse after treatment with standard therapies, including proteasome inhibitors or immunomodulatory agents, have poor prognoses and few treatment options.6

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.7 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. DARZALEX is indicated in Europe for use as monotherapy for the treatment 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. 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,7,8 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,7,8 antibody-dependent cellular phagocytosis9,10 and antibody-dependent cellular cytotoxicity.7,8 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 accompanied by increases in CD4+ and CD8+ T cell numbers in both the peripheral blood and bone marrow.7,11

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, non-Hodgkin’s lymphoma and a solid tumor.