On December 20, 2016 TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, reported that the U.S. Food and Drug Administration (FDA) has granted Priority Review for the niraparib New Drug Application (NDA) (Press release, TESARO, DEC 20, 2016, View Source [SID1234517131]). Niraparib is a PARP inhibitor that is being evaluated as a potential new treatment option for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer following response to platinum-based chemotherapy. The FDA has established a target action date under the Prescription Drug User Fee Act (PDUFA) of June 30, 2017, and is not currently planning to hold an advisory committee meeting to discuss this application.

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Priority Review status is given to drugs that might offer significant improvements in treatment or provide a treatment where no adequate therapy exists.

The niraparib NDA is supported by data from the ENGOT-OV16/NOVA trial, a double-blind, placebo-controlled, international Phase 3 study that enrolled 553 patients with recurrent ovarian cancer who had achieved either a partial response (PR) or a complete response (CR) to their most recent platinum-based chemotherapy. This trial was designed to assess progression free survival (PFS) in patients who were assigned to one of two cohorts based upon germline BRCA mutation status. The full results of the ENGOT-OV16/NOVA trial were presented in detail at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress in Copenhagen on October 8, 2016 and were published simultaneously in The New England Journal of Medicine.

"FDA’s acceptance of the niraparib NDA with a Priority Review designation is an important milestone for TESARO, and represents a significant step in our efforts to bring meaningful therapies to women with ovarian cancer," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "We believe niraparib could become an important new treatment option for patients with recurrent ovarian cancer, and we look forward to working with the FDA during the review process."

The ENGOT-OV16/NOVA trial successfully achieved its primary endpoint in both patient cohorts, demonstrating that niraparib treatment significantly prolonged PFS compared to control. Among patients who were germline BRCA mutation carriers, the niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.27 (95% CI, 0.173-0.410). The median PFS for patients treated with niraparib was 21.0 months, compared to 5.5 months for control (p<0.0001). Among patients in the non-germline BRCA mutant cohort, the niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.45 (95% CI, 0.338-0.607). The median PFS for patients treated with niraparib was 9.3 months, compared to 3.9 months for control (p<0.0001). Based upon the results of this trial, the indication proposed in the NDA provides for the use of niraparib regardless of tumor biomarker status, and it is anticipated that the BRACAnalysis CDx and myChoice HRD tests would be available to physicians as complementary diagnostics.

The most common (≥10%) treatment-emergent grade 3/4 adverse events in the niraparib arm were thrombocytopenia (33.8%), anemia (25.3%), and neutropenia (19.6%) with treatment discontinuation for these events of 3.3%, 1.4% and 1.9%, respectively. Thrombocytopenia was not associated with grade 3/4 bleeding events. The majority of these hematological laboratory abnormalities occurred within the first three cycles; following dose modifications based on individual patient tolerability, the incidence of these lab abnormalities decreased and thrombocytopenia and neutropenia were infrequent beyond cycle 3. The rates of MDS/AML in the niraparib (1.4%) and control (1.1%) arms were similar. There were no deaths among patients during study treatment.

An Expanded Access Program (EAP) for niraparib in the United States is planned to open in January 2017. Expanded access programs enable patients with serious or life-threatening illnesses who do not otherwise qualify for participation in a clinical trial and for whom there are no comparable or satisfactory alternate therapies to access investigational medicines. Through the program, niraparib will be made available for patients with recurrent ovarian cancer following response to platinum-based chemotherapy.

About Niraparib
Niraparib is an oral, once-daily PARP inhibitor that is currently being evaluated in three pivotal trials. TESARO is building a robust niraparib franchise by assessing activity across multiple tumor types and by evaluating several potential combinations of niraparib with other therapeutics. The ongoing development program for niraparib includes a Phase 3 trial in patients with first-line ovarian cancer (the PRIMA trial), a Phase 3 trial for the treatment of patients with germline BRCA-mutated, metastatic breast cancer (the BRAVO trial), and a registrational Phase 2 treatment trial in patients with ovarian cancer (the QUADRA trial). Several combination studies are also underway, including trials of niraparib plus pembrolizumab in metastatic, triple-negative breast cancer and advanced, platinum-resistant ovarian cancer (the TOPACIO trial) and niraparib plus bevacizumab in recurrent, platinum-sensitive ovarian cancer (the ENGOT-OV24/AVANOVA trial). Janssen Biotech has licensed rights to develop and commercialize niraparib specifically for patients with prostate cancer worldwide, except in Japan.

In September 2016, the FDA granted Fast Track designation to niraparib. The FDA Fast Track designation is designed to facilitate the development and expedite the review of medicines that are intended to treat serious conditions and address unmet medical needs. As part of the Fast Track program, the FDA allows for the submission of completed portions of an NDA on an ongoing or rolling basis.

Niraparib is an investigational agent and, as such, has not been approved by the U.S. FDA, European Medicines Agency (EMA), or any other regulatory agencies.

About Ovarian Cancer
Approximately 22,000 women are diagnosed each year with ovarian cancer in the United States, and more than 65,000 women are diagnosed annually in Europe. Ovarian cancer is the fifth most frequent cause of cancer death among women. Despite high response rates to platinum-based chemotherapy in the second-line advanced treatment setting, approximately 85% of patients will experience recurrence within two years. If approved, niraparib may address the difficult "watchful waiting" periods experienced by patients with recurrent ovarian cancer in between cycles of platinum-based chemotherapy.

On December 20, 2016 Bristol-Myers Squibb Company (NYSE: BMY) and PsiOxus Therapeutics, Ltd. (PsiOxus) reported an agreement granting Bristol-Myers Squibb exclusive worldwide rights to NG-348, a pre-clinical stage, "armed" oncolytic virus with the goal of addressing solid tumors (Press release, Bristol-Myers Squibb, DEC 20, 2016, View Source [SID1234517129]). The agreement is subject to clearance under the Hart-Scott-Rodino Antitrust Improvements Act.

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Oncolytic virus therapy utilizes modified viruses like the adenovirus (otherwise known as the common cold virus) that selectively replicate within tumor cells and not within normal tissue. Such viruses stimulate an inflammatory response in the tumor microenvironment, resulting in the accumulation of tumor infiltrating lymphocytes. The NG-348 virus uses PsiOxus’ proprietary Tumor-Specific Immuno-gene Therapy (T-SIGn) platform to "arm" the virus with two additional immuno-therapeutic transgenes.

"PsiOxus has developed a novel platform of tumor-targeted delivery with oncolytic viruses focused on cancer and shares our passion for helping more patients respond to treatment," said Fouad Namouni, M.D., head of Development, Oncology, Bristol-Myers Squibb. "We are excited to bring our deep expertise in Immuno-Oncology to the continued development of NG-348 and to better understand the potential role of oncolytic viruses in enhancing checkpoint blockade in multiple types of cancer in the tumor microenvironment."

"NG-348, represents the first of our T-SIGn armed-viruses," stated John Beadle, M.D., Chief Executive Officer, PsiOxus, "We are thrilled to partner once again with Bristol-Myers Squibb, a leader in Immuno-Oncology, to drive this program into clinical development with the aim of providing a potential treatment to cancer patients."

Under the terms of the agreement, Bristol-Myers Squibb will grant PsiOxus a $50 million upfront payment and will be solely responsible for global clinical development and commercialization activities related to NG-348. PsiOxus is also eligible to receive up to $886 million in development, regulatory and sales-based milestones, as well as royalties on net sales. Bristol-Myers Squibb will also be responsible for providing PsiOxus funding to support activities related to the preclinical development of NG-348.

This agreement follows a June 2016 agreement between the two companies where Bristol-Myers Squibb and PsiOxus entered into an exclusive clinical collaboration to study enadenotucirev, PsiOxus’ systemically administered "unarmed" oncolytic adenovirus therapeutic.

About NG-348

NG-348 is designed to drive T-cell immune responses locally within the tumor microenvironment. It is a transgene-modified variant of PsiOxus’s enadenotucirev virus that encodes two immunomodulatory MiTe proteins in its genome. The two Membrane-integrated T-cell-engaging (MiTe) proteins encoded within NG-348 are:

A membrane anchored full-length human CD80
A membrane anchored antibody fragment specific for the T-cell receptor CD3 protein
When expressed together on the surface of NG-348 infected tumor cells, these two membrane proteins provide both the T-cell receptor (signal 1) and costimulatory (signal 2) activation signals required to polyclonally activate tumor-infiltrating T-cells in an antigen independent manner.

The expression of both transgenes encoded in the NG-348 virus is controlled by the endogenous virus major late promoter. This restricts expression of the proteins to the surface of cells permissive to virus infection (i.e. tumor cells) and prevents off-target expression in the cells from healthy tissues. NG-348 infected tumor cells can potently activate both CD4 and CD8 human T-cells, both in vitro and in a human tumor xenograft model. By contrast, non-tumor cells exposed to NG-348 do not express the MiTe proteins or activate T-cells.

On December 20, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported that Janssen Pharmaceutical K.K. has submitted a New Drug Application to the Ministry of Health, Labor and Welfare (MHLW) in Japan for the use of daratumumab (DARZALEX) for the treatment of adults with relapsed or refractory multiple myeloma (Press release, Genmab, DEC 20, 2016, View Source [SID1234517127]). The submission of the application triggers milestone payments totaling USD 10 million to Genmab from Janssen. Genmab is updating its financial guidance for 2016 to include the milestones. In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop, manufacture and commercialize daratumumab.

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"We are pleased that the first regulatory application for daratumumab in the Asia Pacific region has been submitted and look forward to the decision of the Japanese regulatory authorities," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab. "We continue to be excited by the potential of daratumumab to make a positive impact on the lives of patients with multiple myeloma and their families."

The submission is built around three pivotal studies: the Phase II SIRIUS study (MMY2002), published in The Lancet in April 2016; the Phase III CASTOR study (MMY3004), published in The New England Journal of Medicine in August 2016; the Phase III POLLUX study (MMY3003), published in The New England Journal of Medicine in October 2016; and supported by several other studies.

OUTLOOK
MDKK Revised Guidance Previous Guidance
Revenue 1,720 — 1,770 1,650 — 1,700
Operating expenses (800) — (850) (800) — (850)
Operating income 895 — 945 825 — 875
Cash position at end of year* 3,650 — 3,750 3,650 — 3,750
*Cash, cash equivalents, and marketable securities
Genmab is improving its 2016 financial guidance published on November 21, 2016 due to the inclusion of daratumumab milestones totaling USD 10 million associated with the submission of the regulatory application for daratumumab in relapsed or refractory multiple myeloma in Japan.

Operating Result
We expect our 2016 revenue to be in the range of DKK 1,720 — 1,770 million, an increase of DKK 70 million compared to the previous guidance. We have increased our projected daratumumab milestones to DKK 1,090 million (previously DKK 1,020 million) due to inclusion of USD 10 million in milestone payments triggered by the submission of the regulatory application for daratumumab in relapsed or refractory multiple myeloma in Japan. We expect DARZALEX royalties to remain in the range of DKK 400 — 450 million, which are based on an estimated USD 500 — 550 million of DARZALEX sales in 2016. The remainder of the revenue mainly consists of Arzerra royalties, DuoBody milestones, and non-cash amortization of deferred revenue.

We anticipate that our 2016 operating expenses will remain in the range of DKK 800 — 850 million.

As a result of the increased revenue, we now expect the operating income for 2016 to be approximately DKK 895 – 945 million, compared to DKK 825 – 875 million in the previous guidance.

Cash Position
There is no change to the cash position at the end of 2016 of DKK 3,650 – 3,750 million as we expect to receive payment for the additional milestones shortly after year-end.

Outlook: Risks and Assumptions
In addition to factors already mentioned, the estimates above are subject to change due to numerous reasons, including but not limited to the achievement of certain milestones associated with our collaboration agreements; the timing and variation of development activities (including activities carried out by our collaboration partners) and related income and costs; DARZALEX and Arzerra sales and corresponding royalties to Genmab; fluctuations in the value of our marketable securities; and currency exchange rates. The financial guidance does not include any potential proceeds from future warrant exercises and also assumes that no significant agreements are entered into during 2016 that could materially affect the results.

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 in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy and as a monotherapy 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.

Daratumumab triggers a person’s own immune system to attack the cancer cells, resulting in rapid tumor cell death through multiple immune-mediated mechanisms of action and through immunomodulatory effects, in addition to direct tumor cell death, via apoptosis (programmed cell death).7,8,9,10,11

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 multiple myeloma 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, NKT-cell lymphoma, amyloidosis, and solid tumors. Daratumumab has received two Breakthrough Therapy Designations from the U.S. FDA, for multiple myeloma, as both a monotherapy and in combination with other therapies.