On June 5, 2015 Genmab reported its licensing partner Janssen Biotech, Inc. has initiated a rolling submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for daratumumab (Press release, Genmab, JUN 5, 2015, View Source [SID:1234505254]). The submission is for daratumumab as a treatment for patients with multiple myeloma who have received at least three different lines of therapy including both a proteasome inhibitor and an immunomodulatory agent (IMiD) or who are double refractory to a proteasome inhibitor and an IMiD. A rolling submission allows completed portions of the application to be submitted to the FDA on an ongoing basis. The FDA grants this type of review if the agency determines after a preliminary evaluation of clinical data that the breakthrough therapy may be effective and therefore, will consider reviewing portions of an application before the submission is complete. In August 2012, Genmab and Janssen Biotech, Inc. entered an agreement which granted Janssen a worldwide exclusive license to develop, manufacture and commercialize daratumumab. Janssen is currently the sponsor of all but one study globally.

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The submission includes data from the Phase II study (Sirius MMY2002) of daratumumab in multiple myeloma patients who have received at least three prior lines of therapy including both a proteasome inhibitor and an IMiD or who are double refractory to a proteasome inhibitor and an IMiD. However, safety and efficacy data from the Phase I/II study (GEN501) and safety data from three other studies, have also been included in the BLA submission. Daratumumab received a Breakthrough Therapy Designation (BTD) for this indication from the FDA in May 2013.

"Daratumumab is a highly innovative antibody that holds promise for patients with multiple myeloma, a disease for which there is currently no cure. Today, patients that are double refractory have run out of treatment options and we are very pleased that daratumumab offers the potential to help this group of patients. The initiation of this rolling BLA submission is a landmark in the development of daratumumab and we are working together with Janssen to bring this new treatment option to patients as quickly as we can," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

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 United States (U.S.), following only leukemia and lymphoma.2 Approximately 26,850 new patients will be diagnosed with multiple myeloma and approximately 11,240 people will die from the disease in the U.S. in 2015.3 Globally, it is estimated that 114,251 people will be diagnosed and 80,019 will die from the disease.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

About daratumumab
Daratumumab is an investigational human IgG1k monoclonal antibody (mAb) that binds with high affinity to the transmembrane ectoenzyme, CD38, on the surface of multiple myeloma cells. It induces rapid tumor cell death through diverse mechanisms of action. Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. 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. Daratumumab has been granted Breakthrough Therapy Designation from the US FDA.

(Filing, 10-Q, Generex, JUN 5, 2015, View Source [SID:1234505371])

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On June 5, 2015 Varian Medical Systems reported treating multiple brain metastases with single isocenter RapidArc radiosurgery—a technique for treating several tumors at once rather than one at a time—can deliver results that are equal or comparable to other types of radiosurgery, according to research teams from the University of California, San Diego (UCSD), the University of Birmingham, Alabama (UAB), and other institutions (Press release, InfiMed, JUN 5, 2015, View Source [SID:1234505255]).

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RapidArc Radiosurgery, which is a term for volumetric modulated arc radiosurgery delivered using a medical linear accelerator (linac) from Varian Medical Systems (NYSE: VAR), can also be completed in substantially less time, researchers report. One reason for the speed are the properties of the Varian beam-shaping device, called a multileaf collimator, which features 120 narrow slats that can slide in and out and past each other to produce multiple apertures of virtually any shape, making it possible to target more than one tumor at a time during a treatment. Cone-based and cobalt-based systems like Cyberknife and Gamma Knife are generally limited to targeting one tumor at a time.

In a single-center, retrospective review of 15 patients with multiple brain metastases who were treated with RapidArc radiosurgery between 2009 and 2011, researchers from UCSD noted local tumor control and overall survival rates that were equal or comparable to conventional radiosurgery approaches. The study, published online prior to print in Neurosurgery, reports that no toxicity above grade 2 was observed.1

"Our clinical experience with Rapid Arc Radiosurgery is that it reduced treatment time while accurately conforming the radiation plan to the intended targets," said Clark C. Chen, MD, PhD, chief of stereotactic radiosurgery and vice-chairman of academic affairs, UCSD neurosurgery. "Each treatment of multiple brain metastases in our study was completed in under eight minutes. Reduced treatment time not only optimizes efficiency of institutional work-flow but, more importantly, maximizes patient comfort and the treatment experience."

At the annual meeting of the American Association of Neurological Surgeons (AANS) last month, a poster presentation by Evan Thomas, MD, PhD, from the University of Alabama, Birmingham (UAB), reported on a retrospective review of 34 patients with multiple metastases treated with RapidArc Radiosurgery between 2010 and 2014.2 As described in their Neurosurgery article last year, the UAB team follows a particular planning approach for RapidArc treatments that incorporates the use of non-coplanar arcs to maximize the number of treatment angles, along with key optimization criteria that minimize the amount of low dose "spill" reaching normal brain tissues during treatment.3

"Preliminary results indicated that the toxicity profile associated with these treatments is similar to other modalities, including multi-isocenter approaches, such as Gamma Knife and Cyberknife," Thomas said. "We saw no Grade 4 or 5 toxicity. Grade 3 toxicity occurred in one patient. Grade 2 toxicity occurred in eight patients, consisting mainly of headaches that responded well to steroids. In this patient population, the likelihood of toxicity was mainly associated with previous cranial irradiation treatments and the volume of tissue being irradiated."

Thomas will take part in two presentations about the UAB approach to RapidArc Radiosurgery at the International Stereotactic Radiosurgery Society (ISRS) Congress in Yokohama, Japan next week.4 One will cover a case study wherein RapidArc Radiosurgery was used on five separate occasions to treat a single patient for multiple brain metastases that recurred (Abstract O-59). The second will demonstrate the feasibility of treating numerous (i.e. 15) brain metastases with RapidArc Radiosurgery using Varian’s TrueBeam STx system (Abstract O-48). "Because such treatments can be delivered very quickly, in less than 20 minutes, and with great accuracy, some may find the technique preferable to whole brain radiotherapy or Gamma Knife radiosurgery," Thomas said.

Also at the upcoming ISRS Congress, four other research teams will present abstracts describing work on the use of RapidArc Radiosurgery to create high quality treatment plans for treating targets in the brain: Joe Ho, PhD, and his colleagues at the California Pacific Medical Center in San Francisco, California, will present a practical treatment planning protocol based on the RapidArc technique. The protocol, which is very similar to the UAB model, produces RapidArc Radiosurgery treatment plans that are equal or comparable to Brainlab and Gamma Knife approaches, and much faster to deliver. (Abstract O-55)

A poster presentation by Senthilkumar Natarajan, senior medical physicist, plus his colleagues at the Kovai Medical Center and Hospital in Coimbatore, India, will report on how the UAB approach enabled them to produce treatment plans for cranial targets that achieve a 38% reduction in dose to normal brain tissues, a 30% reduction in the Gradient index (which correlates with how much healthy tissue outside the targeted area is impacted), and a 30% increase in conformity. (Abstract P-77)

Sabbir Hossain, PhD, assistant professor at the University of Oklahoma Health Sciences Center, will present an abstract comparing RapidArc Radiosurgery plans with Gamma Knife plans for treating three patients with four to six brain metastases each. He and his colleagues found that their approach to RapidArc Radiosurgery enabled the production of quality treatment plans that improved on Gamma Knife plans with respect to specific parameters, including conformity index, integral dose, and dose to normal brain tissues. (Abstract O-56)
Yong Cha, MD, PhD, co-director of the Thoracic Oncology and of the Stereotactic Body Radiation Therapy programs at the Norton Cancer Institute in Louisville, Kentucky, will report on the use of RapidArc Radiosurgery to treat ten patients, each with two to eight brain metastases. The Norton team refers to the approach as linac-based single-isocenter cranial radiosurgery (SICR). According to the presentation abstract: "SICR for multiple brain metastases is feasible and demonstrates excellent local control. Given the short treatment time and excellent plan quality, SICR is an excellent treatment option for patients in certain clinical scenarios." (Abstract O-50)
"It is very gratifying to see the amount of clinical research focusing on the promise of treating multiple brain metastases with linac-based RapidArc radiosurgery," said Kolleen Kennedy, president of Varian Oncology Systems. "We are excited to see so much early scientific evidence that this approach is a viable option compared to other forms of radiosurgery because it delivers results that are at least equal or comparable, with substantially greater speed, efficiency, and convenience for patients."

On June 5, 2015 Janssen Research & Development reported Janssen has initiated the rolling submission of its Biologic License Application (BLA) for daratumumab to the U.S. Food and Drug Administration (FDA) 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 (IMiD), or who are double refractory to a PI and an IMiD (Press release, Johnson & Johnson, JUN 5, 2015, View Source [SID:1234505372]). Daratumumab – an investigational human anti-CD38 monoclonal antibody – received Breakthrough Therapy Designation by the U.S. FDA for this set of patients in May 2013. A rolling submission allows the company to submit portions of the regulatory application to the FDA as they are completed.[1]

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In August 2012, Janssen Biotech, Inc. and Genmab A/S entered into an agreement which granted Janssen a worldwide exclusive license to develop, manufacture and commercialize daratumumab. With the exception of one study sponsored globally by the French multiple myeloma cooperative group, Intergroupe Francophone du Myelome (IFM), Janssen is the global sponsor of all current and future clinical studies for daratumumab.

Multiple myeloma is an incurable blood cancer.[2] Approximately 26,850 new patients will be diagnosed with multiple myeloma and approximately 11,240 people will die from the disease in the U.S. in 2015.[3] Patients who relapse after treatment with standard therapies, including PIs or IMiDs, have poor prognoses and few treatment options.[4]

The regulatory submission for daratumumab will be primarily supported by data from the Phase 2 MMY2002 (SIRIUS) monotherapy study announced in May 2015 at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), along with additional data from four other studies, including the Phase 1/2 GEN501 monotherapy study.

"Despite therapeutic advances over the last 10 years, multiple myeloma remains an incurable disease, and many people eventually relapse or grow resistant to available therapies, which has underscored the need for newer medicines with novel mechanisms of action," said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen. "We are proud of the Breakthrough Therapy Designation daratumumab received and look forward to working in close collaboration with the FDA during its review."

Daratumumab is the second medicine in the Janssen oncology portfolio to receive Breakthrough Therapy Designation, which is intended to expedite the development and review time for a potential new medicine. If approved, daratumumab would be commercialized in the U.S. by Janssen Biotech, Inc.

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.[5] Multiple myeloma is the third most common blood cancer in the United States (U.S.), following only leukemia and lymphoma.[6] Globally, it is estimated that 114,251 people will be diagnosed and 80,019 will die from the disease.[7] 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.[8]

About Daratumumab
Daratumumab is an investigational human monoclonal antibody (mAb) that binds with high affinity to the transmembrane ectoenzyme, CD38, on the surface of multiple myeloma cells. It induces rapid tumor cell death through diverse mechanisms of action.[9] Five Phase 3 clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. Additional studies are planned or underway 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 June 4, 2015 OPKO HEALTH, INC. (NYSE:OPK) and Bio-Reference Laboratories, Inc. (NASDAQ:BRLI) reported that the companies have signed a definitive merger agreement under which OPKO will acquire Bio-Reference Laboratories (Press release, Opko Health, JUN 4, 2015, View Source [SID:1234506549]). Bio-Reference Laboratories is the third largest full service clinical laboratory in the United States and is known for its innovative technological solutions and pioneering leadership in the areas of genomics and genetic sequencing. Under the terms of the agreement, which has been approved by the Boards of Directors of both companies, holders of BRLI common stock will receive 2.75 shares of OPKO common stock for each share of BRLI common stock. Based on a closing price of $19.12 per share of OPKO common stock on June 3, 2015, the transaction is valued at approximately $1.47 billion, or $52.58 per share of BRLI common stock. The Companies expect the transaction to be completed during the second half of 2015. Closing of the transaction is subject to approval of Bio-Reference Laboratories’ shareholders and other customary conditions.

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OPKO intends to leverage the national marketing, sales, and distribution resources of Bio-Reference Laboratories to enhance sales of its 4Kscore test, a blood test that provides a patient’s specific personalized risk score for aggressive prostate cancer as well as other OPKO diagnostic products under development.

Through GeneDx, Bio-Reference Laboratories’ genetic sequencing laboratory, and GenPath Diagnostics, its Oncology and Women’s Health business units, Bio-Reference Laboratories has accumulated a vast array of genetic and genomics data that OPKO will make available to industry and academic scientists to enhance their drug discovery and clinical trial programs.

"I have long admired Bio-Reference Laboratories which, for almost 30 years, has enjoyed an impressive record of organic growth through constant innovation and clinical awareness," commented Phillip Frost, M.D., OPKO’s Chairman and Chief Executive Officer. "Bio-Reference Laboratories is a true success story that has culminated in cutting edge diagnostic solutions accompanied by a worldwide franchise in the diagnosis of rare diseases. GeneDx was the first commercial laboratory to offer next generation sequencing for rare disorders and almost a quarter of a million patients have benefited from these services including almost 20,000 patients who have undergone exome analysis. Their newly introduced sequencing services for use in oncology are both innovative and impressive."

"Over the years we have learned that diagnostics are integral to drug discovery," commented Marc Grodman, M.D., Bio-Reference Laboratories’ Chairman, CEO and President. "This has never been more apparent than today when new sequencing technologies have afforded us the opportunity to understand the biological basis of disease in far greater depth. At Bio-Reference Laboratories we have prided ourselves in finding disruptive diagnostic solutions that are clinically relevant. Dr. Frost is a visionary in the pharmaceutical world who, during a legendary career, has demonstrated the foresight to see new clinical applications for therapeutics before others. I am thrilled that I will be working and learning from him in the coming years as we seek to leverage our outstanding capabilities to improve lives of patients. In addition to identifying a synergistic partner for the value we have built over the past three decades, we are pleased that our shareholders will be rewarded by being able to share in the upside of the combined company."

OPKO intends to allow laboratory operations to continue seamlessly but with enhancement from OPKO’s pipeline of diagnostic products. The current diagnostic services of OPKO will be merged with the Bio-Reference Laboratories operations throughout the country. Bio-Reference Laboratories’ national presence will add valuable distribution capability to OPKO’s diagnostic services. Bio-Reference Laboratories is a full service clinical laboratory that can provide key areas of opportunity for OPKO’s services. Moreover, the seasoned management team at Bio-Reference Laboratories will bring valuable market intelligence to the combined operations.

Dr. Grodman continued, "Bio-Reference Laboratories has been a pioneer in commercial laboratory use of next generation sequencing for diagnostic purposes. GeneDx believes it was the first commercial laboratory in the world to offer next generation genetic sequencing panels based on specific clinical symptoms; it has maintained its leadership position in offering advanced panels, sophisticated analysis, in-depth reporting, and by scaling these tools to a high-volume commercial environment. Bio-Reference Laboratories has accumulated a plethora of genetic and genomics data that will be invaluable to the drug discovery programs at OPKO and other drug developers. The Bio-Reference Laboratories data is diagnostic, or disease-related, and therefore provides an important connection between disease, treatment and cure."