On May 23, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported that the European Commission (EC) has granted a conditional marketing authorization for first-in-class CD38 antibody DARZALEX (daratumumab) (Press release, Genmab, MAY 23, 2016, View Source [SID:1234512691]).

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The conditional approval 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. The EC approval follows a positive opinion issued for DARZALEX by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) in April 2016. Conditional marketing authorizations are granted by the EMA for medicines where the benefit of immediate availability outweighs the risk of less comprehensive data than normally required. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

DARZALEX is the first human CD38 monoclonal antibody (mAb) approved in Europe. The European approval follows the November 2015 U.S. Food and Drug Administration (FDA) approval of DARZALEX 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. In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop, manufacture and commercialize DARZALEX.

The marketing authorization was based on data from the Phase II study (SIRIUS MMY2002, published in The Lancet in January 2016), the Phase I/II GEN501 monotherapy study (published in The New England Journal of Medicine in August 2015) and data from three additional supportive studies. These studies included heavily pre-treated patients with relapsed and refractory multiple myeloma who had exhausted other approved treatment options and whose disease was progressive at enrolment. Findings from a combined efficacy analysis of the GEN501 and MMY2002 (SIRIUS) trials demonstrated that after a mean follow-up of 14.8 months, the estimated median overall survival (OS) for single-agent daratumumab (16 mg/kg) in these heavily pre-treated patients was 20 months (95 percent Confidence Interval, 15 months to not yet estimable). The overall response rate (ORR) for the combined analysis was 31 percent, and 83 percent of patients achieved stable disease or better.1

"At Genmab we are driven by a desire to improve the quality of life for cancer patients and their families. The approval of the marketing application for DARZALEX provides the opportunity to do just that for multiple myeloma patients living in the EU and represents a landmark event for these patients and their families, as well as for Genmab and Janssen," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

Daratumumab demonstrated a clinically manageable safety profile. The most commonly occurring adverse reactions (in 20 percent or more of patients in three pooled clinical studies) were infusion-related reactions (IRRs), fatigue, pyrexia, cough, nausea, back pain, upper respiratory tract infection, anemia, neutropenia (abnormally low levels of neutrophils, a type of white blood cell) and thrombocytopenia (abnormally low levels of platelets in the blood).2
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.2 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.2

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.3 Multiple myeloma is the third most common blood cancer in the U.S., after leukemia and lymphoma.4 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 2015.5 Globally, it was estimated that 124,225 people would be diagnosed and 87,084 would die from the disease in 2015.6 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.7 Patients who relapse after treatment with standard therapies, including proteasome inhibitors or immunomodulatory agents, have poor prognoses and few treatment options.8

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.2 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,2,9 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,2,9 antibody-dependent cellular phagocytosis10,11 and antibody-dependent cellular cytotoxicity.2,9 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.2

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.

On May 23, 2016 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that it gained approval by the Japanese Ministry of Health, Labour and Welfare (MHLW) on May 23, 2016, for "advanced or recurrent cervical cancer," as new additional indication for the anti-cancer agent / anti-VEGF humanized monoclonal antibody, "AVASTIN I.V. Infusion 100 mg/4 mL and 400 mg/16 mL" [generic name: bevacizumab (genetic recombinant) for Infusion] (Avastin) (Press release, Chugai, MAY 23, 2016, View Source [SID:1234512672]).

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In Japan, Avastin is currently marketed for the indications of "unresectable advanced or recurrent colorectal cancer," "unresectable advanced or recurrent non-squamous non-small cell lung cancer," "inoperable or recurrent breast cancer," "malignant glioma" and "ovarian cancer." On September 14, 2015, Avastin for advanced or recurrent cervical cancer has been designated as orphan drug and priority review product.

This approval was obtained based on the results of overseas phase III studies (The GOG-0240 study) and Japanese phase II study (The JO29569 study).

The GOG-0240 study evaluated the efficacy and safety profile of standard chemotherapies (paclitaxel and cisplatin or paclitaxel and nogitecan) with or without Avastin in 452 patients with persistent, recurrent or metastatic cervical cancer.
The study met its primary endpoint of improving overall survival (OS) with a statistically significant 26 percent reduction in the risk of death, representing a median gain in survival of 3.9 months, compared with those who received chemotherapy alone [16.8 months vs. 12.9 months; HR=0.74, stratified log-rank test, one-sided p=0.0066 (significance level: 0.0140)]
The study showed that patients who received Avastin plus chemotherapy had a significant improvement of progression free survival (PFS) compared with those who received chemotherapy alone ［8.3 months vs. 6.0 months; HR=0.66, stratified log-rank test, p<0.0001］.
The study showed that patients who received Avastin plus chemotherapy had a significantly higher rate of tumor shrinkage (objective response rate, ORR) compared with those who received chemotherapy alone [45.4% (95% CI: 38.8-52.1%) vs. 33.8% (95% CI 27.6-40.4%); Chi-squared test, p=0.0117].
The safety profile in the study was consistent with previous reports of Avastin, except for an increase in gastrointestinal-vaginal fistulas observed in patients who received Avastin plus chemotherapy compared to those who received chemotherapy alone (8.3% vs. 0.9% respectively). All patients with gastrointestinal-vaginal fistulas had a history of prior pelvic radiation.
The JO29569 study evaluated the tolerability, safety and efficacy of Avastin plus paclitaxel and cisplatin. Within eight Japanese patients with advanced or recurrent cervical cancer enrolled in the study, seven patients were evaluated, and one patient was excluded before the start of the study. As a result, the tolerability of Avastin plus chemotherapy was confirmed, and the harmful phenomenon to become the problem was not accepted, and no new safety finding were observed.

"We are proud that Avastin received an approval for cervical cancer as the sixth indication in Japan, which will contribute to the treatment of many cancer patients," said Chugai’s Director and Executive Vice President, Dr. Yutaka Tanaka. "We believe that Avastin would bring great news for the treatment of advanced or recurrent cervical cancer, which has limited treatment options and has not seen any progress for the last ten years."

Avastin is approved in Europe for the treatment of advanced stages of breast cancer, colorectal cancer, non-small cell lung cancer, renal cell cancer, ovarian cancer and cervical cancer, and is available in the US for the treatment of colorectal cancer, non-small cell lung cancer, renal cell cancer, recurrent glioblastoma, cervical cancer and recurrent ovarian cancer. Avastin is approved for cervical cancer in 67 countries (as of January, 2016).

The number of patients newly diagnosed as cervical cancer in Japan continues to rise each year and the annual average in 2015-2019 is estimated to be approximately 10,600.*

As the top pharmaceutical company in the field of oncology in Japan, Chugai is convinced that Avastin can contribute to the treatment of patients with "advanced or recurrent cervical cancer," a disease with high unmet medical need, by providing a new therapeutic option.

* T. Sobue, et al., Cancer White Paper 2012, Shinoharashinsha Inc.

Drug Information

The underlined descriptions are newly added.

Brand name: Avastin for intravenous infusion 100 mg/4 mL
Avastin for intravenous infusion 400 mg/16 mL
Generic name: bevacizumab (genetic recombination)
Indications, dosage and administration:
Indications Dosage and Administration
Unresectable advanced or recurrent colorectal cancer The usual adult dosage is 5 mg/kg (body weight) or 10 mg/kg (body weight) of bevacizumab (recombinant) per intravenous infusion in combination with other antineoplastic agents. The administration interval of AVASTIN should be 2 weeks or longer.
The usual adult dosage is 7.5 mg/kg (body weight) of bevacizumab (recombinant) per intravenous infusion in combination with other antineoplastic agents. The administration interval of AVASTIN should be 3 weeks or longer.
Unresectable advanced or recurrent non-squamous non-small cell lung cancer The usual adult dosage is 15 mg/kg (body weight) of bevacizumab (recombinant) per intravenous infusion in combination with other antineoplastic agents. The administration interval of AVASTIN should be 3 weeks or longer.
Ovarian cancer
Advanced or recurrent cervical cancer
Inoperable or recurrent breast cancer The usual adult dosage is 10 mg/kg (body weight) of bevacizumab (recombinant) per intravenous infusion in combination with paclitaxel. The administration interval of AVASTIN should be 2 weeks or longer.
Malignant glioma The usual adult dosage per intravenous infusion of bevacizumab (recombinant) is 10 mg/kg (body weight) every 2 weeks or 15 mg/kg (body weight) every 3 weeks. The administration interval of AVASTIN should be appropriately extended on the basis of patient condition.

On May 23, 2016 Astellas Pharma Inc. (President and CEO: Yoshihiko Hatanaka; Headquarters: Tokyo; TSE: 4503; "Astellas"), Daiichi Sankyo Company, Limited (President and CEO: Joji Nakayama; Headquarters: Tokyo; TSE: 4568; "Daiichi Sankyo"), and Takeda Pharmaceutical Company Limited (President and CEO: Christophe Weber; Headquarters: Osaka; TSE: 4502; "Takeda") reported that they have entered into a joint research agreement (Press release, Astellas, MAY 23, 2016, http://www.astellas.com/en/corporate/news/detail/astellas-daiichi-sankyo-and-ta.html [SID:1234512671]). It is an agreement to comprehensively acquire and analyze fundamental biomarker*1 data on healthy adult volunteers in order to optimize and accelerate the development of innovative medicines.

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Biomarkers are used in patient stratification, investigation of a drug’s mechanism of action, and efficacy and safety indices, and are utilized in a wide variety of scenarios, ranging from the exploration stage of drug candidacy to clinical studies and daily diagnostics. However, fundamental biomarker data from healthy adults, which can be used for comparing and contrasting with patients in the preclinical and clinical stages, has not been sufficiently accumulated globally, and further enhancement of data construction is expected.

Based on this agreement, Astellas, Daiichi Sankyo, and Takeda will comprehensively acquire fundamental data from healthy adult volunteers that is required for clinical studies using protein and metabolite biomarkers, and undertake joint analysis thereon. Samples will be acquired at a clinical research organization associated with Leiden University in the Netherlands and be under the supervision of Dr. Thomas Hankemeier, Professor at Leiden University. The analysis results will be mainly utilized in the companies’ therapeutic areas of focus*2. Data gained from this analysis will be publicized so that it may be widely utilized in various types of drug discovery research to meet patients’ unmet needs.

Astellas, Daiichi Sankyo, and Takeda aim to contribute to the enhancement of health and welfare of people around the world through creating innovative medicine. Through this joint research, it will become possible to establish a base of comprehensive biomarker data— something that is difficult for individual pharmaceutical companies to do— as well as lead to more effective drug discovery by using a translational research*3 approach. The three companies will contribute to the optimization and acceleration of innovation in Japan-originated drug discovery through this collaboration as pharmaceutical companies with research bases in Japan.

On May 23, 2016 Ionis Pharmaceuticals, Inc. (NASDAQ: IONS) and The University of Texas MD Anderson Cancer Center reported the formation of a strategic alliance to discover and develop novel cancer therapeutics (Press release, Ionis Pharmaceuticals, MAY 23, 2016, View Source [SID:1234512670]).

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Combining advances made with Ionis’ antisense technology, which provides enhanced potency for effectively engaging targets in solid and liquid tumors, with MD Anderson’s expertise will allow Ionis and MD Anderson to develop novel therapeutic strategies to treat patients with a variety of cancers.

"MD Anderson is dedicated to accelerating the end of cancer. As part of our Moon Shots Program, we identified many new, traditionally undruggable cancer targets, which could offer a potentially fresh approach to treating cancer," said Gordon Mills, M.D., Ph.D., chair, systems biology at MD Anderson. "This collaboration allows our experts to take advantage of a novel technology capable of targeting undruggable targets that we believe will add to our ability to develop therapeutic strategies that will transform patient outcomes."

Mills is co-leader of the Breast and Ovarian Cancer Moon Shot, one of 12 in MD Anderson’s effort to reduce cancer deaths by accelerating conversion of scientific discoveries into new therapies, prevention approaches and early detection.

"MD Anderson has undertaken groundbreaking work in identifying novel cancer targets and building pre-clinical cancer models that will streamline our collective drug discovery efforts. Their genetically defined patient populations should greatly shorten the overall development timelines and enhance our drug discovery efforts as we move our programs forward," said Brett Monia, senior vice president, antisense drug discovery at Ionis Pharmaceuticals. "Our Generation 2.5 chemistry coupled with the expertise of a world leading cancer center, like MD Anderson, will drive our oncology drug development program and pipeline."

In the collaboration, Ionis and MD Anderson will work together to validate novel undruggable cancer targets selected based on human genomic data. Ionis will lead the drug discovery efforts against mutually agreed upon novel targets and MD Anderson will lead development activities through clinical proof of concept. Following clinical proof of concept, Ionis and MD Anderson plan to identify a partner to complete development and to commercialize each drug with Ionis leading business development efforts.

"We are excited to have MD Anderson as a strategic partner for our cancer franchise. This alliance allows Ionis and MD Anderson to combine their collective expertise and resources to identify and ultimately develop novel anti-cancer drugs," said Sarah Boyce, chief business officer at Ionis Pharmaceuticals. "This alliance enables Ionis and MD Anderson to focus on their respective areas of expertise, thereby facilitating rapid progress in moving each drug through the clinic. We believe this collaboration has the opportunity to create novel therapeutic agents that can provide great benefit for cancer patients."