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Exelixis Announces European Medicines Agency Acceptance of Marketing Authorization Application for Cabozantinib as a Treatment for Advanced Renal Cell Carcinoma

On January 28, 2016 Exelixis, Inc. (NASDAQ:EXEL) reported that the European Medicines Agency (EMA) has accepted for review -the Marketing Authorization Application (MAA) for cabozantinib as a treatment for patients with advanced renal cell carcinoma (RCC) who have received one prior therapy (Press release, Exelixis, JAN 28, 2016, View Source [SID:1234508899]). The completion of the MAA validation process confirms that the submission is sufficient to permit a substantive review for marketing authorization in the European Union.

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The EMA’s Committee for Medicinal Products for Human Use (CHMP) previously granted accelerated assessment to cabozantinib for advanced RCC. As a result, the MAA will be eligible for a 150-day review, versus the standard 210 days (excluding clock stops when information is requested by CHMP).

The MAA is based on the results of METEOR, a phase 3 pivotal trial comparing cabozantinib to everolimus in patients with advanced RCC who experienced disease progression following treatment with a VEGF receptor tyrosine kinase inhibitor. In July 2015, Exelixis announced top-line results from METEOR demonstrating that the trial had met its primary endpoint of improving progression-free survival; compared with everolimus, a standard of care for second line RCC therapy, cabozantinib was associated with a 42% reduction in the rate of disease progression or death. These data were later presented at the European Cancer Congress in September 2015 and concurrently published in The New England Journal of Medicine.

In the United States, in late December 2015, Exelixis announced that it completed the submission of its rolling New Drug Application (NDA) for cabozantinib as a treatment for patients with advanced RCC who have received one prior therapy. The U.S. Food and Drug Administration (FDA) subsequently determined the NDA to be sufficiently complete to permit a substantive review, granted Priority Review, and assigned a Prescription Drug User Fee Act action date of June 22, 2016. The NDA will be considered officially filed 60 days from the date of the completion of the submission, or February 20, 2016. The FDA previously granted Breakthrough Therapy and Fast Track designations to cabozantinib for its potential advanced RCC indication.

Cabozantinib is currently marketed in capsule form under the brand name COMETRIQ in the United States for the treatment of progressive, metastatic medullary thyroid cancer (MTC), and in the European Union for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. COMETRIQ is not indicated for patients with RCC. In the METEOR trial, and all other cancer trials currently underway, Exelixis is investigating a tablet formulation of cabozantinib distinct from the COMETRIQ capsule form. The tablet formulation of cabozantinib is the subject of the MAA for advanced RCC.

About Advanced Renal Cell Carcinoma

The American Cancer Society’s 2015 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; however, the five-year survival rate for patients with advanced or late-stage metastatic RCC is under 10 percent, with no identified cure for the disease.3

Until the introduction of targeted therapies into the RCC setting a decade ago, treatments for metastatic RCC had historically been limited to cytokine therapy (e.g., interleukin-2 and interferon). In the second and later-line settings, which encompass approximately 17,000 drug-eligible patients in the U.S. and 37,000 globally,4 two small-molecule therapies and an immune checkpoint inhibitor have been approved for the treatment of patients with advanced RCC who have received prior systemic therapy. The currently approved small-molecule agents have shown little differentiation in terms of efficacy and have demonstrated only modest progression-free survival benefit in patients refractory to sunitinib, a commonly-used first-line therapy.

The majority of clear cell RCC tumors exhibit down-regulation of von Hippel-Lindau protein function, either due to gene inactivation or epigenetic silencing, resulting in a stabilization of the hypoxia-inducible transcription factors and consequent up-regulation of VEGF, MET and AXL.5 The up-regulation of VEGF may contribute to the angiogenic nature of clear cell RCC, and expression of MET or AXL may be associated with tumor cell viability, a more invasive tumor phenotype and reduced overall survival. 6 Up-regulation of MET and AXL in clear cell RCC has also been shown to occur in response to treatment with VEGF receptor TKIs in preclinical models, indicating a potential role for MET and AXL in the development of resistance to these therapies.7

About Cabozantinib

Cabozantinib inhibits the activity of tyrosine kinases including MET, VEGF receptors, AXL and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis and maintenance of the tumor microenvironment.

Cabozantinib, marketed under the brand name COMETRIQ, is currently approved by the U.S. Food and Drug Administration for the treatment of progressive, metastatic medullary thyroid cancer (MTC).

The European Commission granted COMETRIQ conditional approval for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. Similar to another drug approved in this setting, the approved indication states that for patients in whom Rearranged during Transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decisions.

Important Safety Information, including Boxed WARNINGS

WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

Serious and sometimes fatal gastrointestinal perforations and fistulas occur in COMETRIQ-treated patients.

Severe and sometimes fatal hemorrhage occurs in COMETRIQ-treated patients.

COMETRIQ treatment results in an increase in thrombotic events, such as heart attacks.

Wound complications have been reported with COMETRIQ.

COMETRIQ treatment results in an increase in hypertension.

Osteonecrosis of the jaw has been observed in COMETRIQ-treated patients.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES) occurs in patients treated with COMETRIQ.

The kidneys can be adversely affected by COMETRIQ. Proteinuria and nephrotic syndrome have been reported in patients receiving COMETRIQ.

Reversible Posterior Leukoencephalopathy Syndrome has been observed with COMETRIQ.

Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.

COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.

COMETRIQ can cause fetal harm when administered to a pregnant woman.

Adverse Reactions – The most commonly reported adverse drug reactions (≥25%) are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Please see full U.S. prescribing information, including Boxed WARNINGS, at www.COMETRIQ.com/downloads/Cometriq_Full_Prescribing_Information.pdf.

Please refer to the full European Summary of Product Characteristics for full European Union prescribing information, including contraindication, special warnings and precautions for use at www.sobi.com once posted.

FDA approves first drug to show survival benefit in liposarcoma

The U.S. Food and Drug Administration today approved Halaven (eribulin mesylate), a type of chemotherapy, for the treatment of liposarcoma (a specific type of soft tissue sarcoma) that cannot be removed by surgery (unresectable) or is advanced (metastatic) (FDA.gov, FDA approves first drug to show survival benefit in liposarcoma, JAN 28, 2016, View Source [SID:1234508897]). This treatment is approved for patients who received prior chemotherapy that contained an anthracycline drug.

"Halaven is the first drug approved for patients with liposarcoma that has demonstrated an improvement in survival time," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. "The clinical trial data the FDA reviewed indicates that Halaven increased overall survival by approximately seven months, offering patients a clinically meaningful drug."

Soft tissue sarcoma (STS) is a disease in which cancer cells form in the soft tissues of the body, including the muscles, tendons, fat, blood vessels, lymph vessels, nerves and tissues around joints. Liposarcoma is a specific type of STS that occurs in fat cells. STS can form almost anywhere in the body, but is most common in the head, neck, arms, legs, trunk and abdomen. In 2014, an estimated 12,000 cases of STS were diagnosed in the United States, according to the National Cancer Institute.

The efficacy and safety of Halaven were evaluated in 143 clinical trial participants with advanced liposarcoma that was unresectable or had spread to nearby lymph nodes (locally advanced) or other parts of the body (metastatic), and who had been treated with chemotherapy. Participants were treated with either Halaven or another chemotherapy drug called dacarbazine until their disease spread or until they were no longer able to tolerate the side effects of treatment. The study was designed to measure the length of time from the start of treatment until a patient’s death (overall survival). The median overall survival for patients with liposarcoma receiving Halaven was 15.6 months compared to 8.4 months for those who received dacarbazine.

The most common side effects among participants treated with Halaven were fatigue, nausea, hair loss (alopecia), constipation, certain nerve damage causing weakness or numbness in the hands and feet (peripheral neuropathy), abdominal pain and fever (pyrexia). Halaven may also cause low levels of infection-fighting white blood cells (neutropenia) or decreased levels of potassium or calcium.

Serious side effects from treatment with Halaven may include a decrease in white blood cell count, which can increase the risk of serious infections that could lead to death; numbness, tingling or burning in the hands and feet (neuropathy); harm to a developing fetus; as well as changes in heartbeat (QTc prolongation), that may also lead to death.

The FDA granted the Halaven application priority review status, intended to facilitate and expedite the development and review of certain drugs in light of their potential to benefit patients with serious or life-threatening conditions. Halaven also received orphan drug designation, which provides incentives such as tax credits, user fee waivers, and eligibility for exclusivity to assist and encourage the development of drugs for rare diseases.

Halaven is marketed by Eisai based in Woodcliff Lake, New Jersey.

CheckMate -141, a Pivotal Phase 3 Opdivo (nivolumab) Head and Neck Cancer Trial, Stopped Early

On January 28, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported that a randomized Phase 3 study evaluating Opdivo (nivolumab) versus investigator’s choice in patients with recurrent or metastatic platinum-refractory squamous cell carcinoma of the head and neck (SCCHN) was stopped early because an assessment conducted by the independent Data Monitoring Committee (DMC) concluded that the study met its primary endpoint, demonstrating superior overall survival (OS) in patients receiving Opdivo compared to the control arm (Press release, Bristol-Myers Squibb, JAN 28, 2016, View Source [SID:1234508886]). The company looks forward to sharing these data with health authorities soon.

"With the results of CheckMate -141, Opdivo moves closer to providing a potential treatment option for patients with head and neck cancer, a cancer with a high unmet need and limited treatment options," said Michael Giordano, M.D., senior vice president, head of Oncology Development, Bristol-Myers Squibb. "We look forward to continuing to advance the Opdivo clinical development program in hard-to-treat cancers, such as head and neck cancer."

CheckMate -141 investigators have been informed of the decision to stop the trial early and Bristol-Myers Squibb is working to ensure that eligible patients be provided the opportunity to continue or start treatment with Opdivo as part of the company’s commitment to providing patient access to Opdivo, and characterizing long-term survival. The company will complete a full evaluation of the final CheckMate -141 data, and work with investigators on the future presentation and publication of the results.

About CheckMate -141

CheckMate -141 is a Phase 3, open-label, randomized study of Opdivo versus investigator’s choice of therapy in previously treated patients with SCCHN who have tumor progression on or within 6 months of platinum therapy in the primary, recurrent, or metastatic setting. The trial randomized 361 patients 2:1 to receive either Opdivo 3 mg/kg intravenously every two weeks or investigator’s choice (cetuximab/methotrexate/docetaxel) until documented disease progression or unacceptable toxicity. The primary endpoint is OS. Secondary endpoints include objective response rate and progression free survival.

About Head & Neck Cancer

Head and neck cancer is the seventh most common cancer globally, with an estimated 400,000 to 600,000 new cases per year and 223,000 to 300,000 deaths per year. The five-year survival rate is reported as less than four percent for metastatic Stage IV disease. SCCHN accounts for approximately 90 percent of all head and neck cancers with global incidence expected to increase by 17 percent between 2012 and 2022. Risk factors for SCCHN include tobacco and alcohol consumption and the increasing role of Human Papilloma Virus (HPV) infection leading to rapid increase in oropharyngeal SCCHN in Europe and North America. Quality of life is often impacted for SCCHN patients as physiological function (breathing, swallowing, eating, drinking), personal characteristics (appearance, speaking, voice), sensory function (taste, smell, hearing), and psychological/social function can be affected.

Bristol-Myers Squibb Reports Fourth Quarter and Full Year 2015 Financial Results

On January 28, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported results for the fourth quarter and full year of 2015, which were highlighted by strong sales for Opdivo, Eliquis and Orencia and continued advances in the company’s Immuno-Oncology portfolio (Press release, Bristol-Myers Squibb, JAN 28, 2016, View Source [SID:1234508885]).

"We have had an unprecedented year in Immuno-Oncology, delivered strong overall business performance and made strategic investments that position the company well for growth," said Giovanni Caforio, M.D., chief executive officer, Bristol-Myers Squibb. "We are looking forward to 2016 as an exciting year to continue our leadership in Immuno-Oncology, drive performance of our in-line products and continue to advance our diversified R&D portfolio."

FOURTH QUARTER FINANCIAL RESULTS

Bristol-Myers Squibb posted fourth quarter 2015 revenues of $4.3 billion, an increase of 1% compared to the same period a year ago. Global revenues increased 6% adjusted for foreign exchange impact.

U.S. revenues increased 9% to $2.3 billion in the quarter compared to the same period a year ago. International revenues decreased 7%. When adjusted for foreign exchange impact, international revenues increased 3%.

Gross margin as a percentage of revenues was 77.8% in the quarter compared to 77.3% in the same period a year ago.

Marketing, selling and administrative expenses, which includes advertising and product promotion expenses, increased 10% to $1.5 billion in the quarter.

Research and development expenses increased 61% to $1.9 billion in the quarter due to higher charges resulting from business development transactions and an in-process research and development (IPRD) impairment.

The effective tax benefit rate was 59.7% in the quarter, compared to 145.0% in the fourth quarter last year. Income taxes in both periods include net tax benefits attributed to specified items and the R&D credit for the full year.

The company reported a net loss attributable to Bristol-Myers Squibb of $138 million, or $0.08 per share, in the quarter compared to net earnings of $13 million, or $0.01 per share, a year ago. Results in the current quarter include charges resulting from the Five Prime Therapeutics, Inc. and Cardioxyl Pharmaceuticals, Inc. business development transactions ($0.24 per share after tax) and non-cash charges resulting from an IPRD impairment for BMS-986020, an investigational oral lysophosphatidic acid 1 receptor antagonist, in fibrosis and the transfer of the Erbitux business in North America to Eli Lilly and Company ($0.14 per share after tax).

The company reported non-GAAP net earnings attributable to Bristol-Myers Squibb of $647 million, or $0.38 per share, in the fourth quarter, compared to $771 million, or $0.46 per share, for the same period in 2014. An overview of specified items is discussed under the "Use of Non-GAAP Financial Information" section.

Cash, cash equivalents and marketable securities were $8.9 billion, with a net cash position of $2.2 billion, as of December 31, 2015.

FOURTH QUARTER PRODUCT AND PIPELINE UPDATE

Global revenues for the fourth quarter of 2015, compared to fourth quarter 2014, were driven by Opdivo, which grew by $470 million; Eliquis, which grew by $321 million; Daklinza and Sunvepra, which grew by $251 million, Orencia, which grew 22%; and Sprycel, which grew 8%.

Opdivo

In January, the company announced that a randomized Phase 3 study evaluating Opdivo versus investigator’s choice in patients with recurrent or metastatic platinum-refractory squamous cell carcinoma of the head and neck (CheckMate -141) was stopped early because an assessment conducted by the independent Data Monitoring Committee concluded that the study met its primary endpoint, demonstrating superior overall survival (OS) in patients receiving Opdivo compared to the control arm. The company looks forward to sharing these data with health authorities soon.

In January, the company announced the U.S. Food and Drug Administration (FDA) has approved Opdivo in combination with Yervoy for the treatment of patients with BRAF v600 wild-type (WT) and BRAF v600 mutation-positive unresectable or metastatic melanoma. This approval expands the original indication for the Opdivo + Yervoy Regimen for the treatment of patients with BRAF v600 WT unresectable or metastatic melanoma to include patients, regardless of BRAF mutational status, based on data from the Phase 3 CheckMate -067 trial which evaluated progression-free survival (PFS) and OS as co-primary endpoints. This indication is approved under accelerated approval based on PFS. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

In December, the company and its partner, Ono Pharmaceutical Co. Ltd., announced that Ono received manufacturing and marketing approval for Opdivo in Japan for the treatment of patients with unresectable, advanced or recurrent non-small cell lung cancer.

In December, the company and its partner, Seattle Genetics, Inc., announced the companies have initiated a Phase 1/2 clinical trial of ADCETRIS (brentuximab vedotin) in combination with Opdivo for patients with CD30-expressing relapsed or refractory B-cell and T-cell non-Hodgkin lymphomas, including diffuse large B-cell lymphoma, peripheral T-cell lymphoma and cutaneous T-cell lymphoma. This is the second of two trials being conducted under a previously announced clinical trial collaboration agreement between the company and Seattle Genetics, Inc.

In November, the company announced the FDA approved Opdivo injection, for intravenous use, for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy. Opdivo is the first and only PD-1 inhibitor to deliver significant OS in patients with advanced RCC who have received prior anti-angiogenic therapy. The approval, which was granted Breakthrough Therapy Designation by the FDA, was based on data from CheckMate -025, an open-label, randomized Phase 3 study evaluating Opdivo versus everolimus in patients with advanced RCC who have received prior anti-angiogenic therapy.
In November, the company announced the FDA approved Opdivo injection, for intravenous use, as a single-agent for the treatment of patients with BRAF v600 WT unresectable or metastatic melanoma. The approval is based on data from the Phase 3 trial, CheckMate -066, which evaluated OS as the primary endpoint in treatment-naïve patients with BRAF WT unresectable or metastatic melanoma compared to chemotherapy (dacarbazine). Separately, the company announced the FDA issued a Complete Response Letter for its supplemental Biologics License Application (sBLA) for Opdivo as a single agent for the treatment of previously untreated patients, specifically those with BRAF v600 mutation positive unresectable or metastatic melanoma. The company submitted data for Opdivo in BRAF v600 mutation-positive metastatic melanoma, which was the subject of the FDA’s Complete Response Letter.

In November, the company announced that the European Medicines Agency (EMA) validated a type II variation application which seeks to extend the current indication for Opdivo to include the treatment of adult patients with advanced RCC after prior therapy. Validation of the application confirms the submission is complete and begins the EMA’s centralized review process. The type II variation submitted is based on data from CheckMate -025, a Phase 3 study that evaluated, as the primary endpoint, the OS of Opdivo versus everolimus, a current standard of care, in advanced or metastatic clear-cell RCC after prior anti-angiogenic treatment.

In November, the company announced results from multiple clinical trials at the Society for Melanoma Research 2015 International Congress in San Francisco, California.
CheckMate -066 – In the study evaluating Opdivo as a single agent versus dacarbazine in patients with previously untreated, BRAF WT unresectable or metastatic melanoma, Opdivo continued to demonstrate superior OS versus dacarbazine with 57.7% of patients alive at two years compared to 26.7% of patients treated with dacarbazine. The safety profile of Opdivo was consistent with prior studies.

Study 004 – In the study evaluating Opdivo in combination with Yervoy in patients with unresectable or metastatic melanoma on which the proof of concept for Opdivo + Yervoy regimen approval was based, data from the longest follow-up of the regimen from various Phase 1 cohorts showed a three-year OS rate of 68% across Phase 1 dosing cohorts. The frequency of treatment-related adverse events (AE) in the study were similar between cohorts and was consistent with the Phase 2 and 3 trials for the combination therapy.

Yervoy

In October, the company announced the FDA approved Yervoy 10 mg/kg for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection including total lymphadenectomy. The approval is based on clinical data from a pivotal Phase 3 trial, CA184-029 (EORTC 18071), initiated in 2008 by the European Organization for Research and Treatment of Cancer evaluating the 10 mg/kg dose in the adjuvant setting.

Empliciti

In November, the company and its partner, AbbVie, Inc., announced the FDA approved Empliciti for the treatment of multiple myeloma as combination therapy with Revlimid and dexamethasone in patients who have received one to three prior therapies. The approval of this first and only immunostimulatory antibody for multiple myeloma is based on data from the randomized, open-label, Phase 3, ELOQUENT-2 study, which demonstrated the combination of Empliciti with Revlimid and dexamethasone delivered a 30% reduction in the risk of disease progression or death compared to dexamethasone alone.

In December, the company announced extended follow-up data and a pre-specified interim OS analysis of Empliciti in combination with Revlimid and dexamethasone in patients with relapsed or refractory multiple myeloma from ELOQUENT-2. The follow-up data demonstrated a 44% relative improvement in PFS at three years, which was consistent with the pivotal two-year analysis. The Empliciti combination delayed the need for subsequent myeloma therapy by a median of one year compared to dexamethasone alone. Data were presented at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in Orlando, Florida.

Daklinza

In November, the company announced results from the Phase 3 ALLY-3+ trial investigating a regimen of Daklinza in combination with sofosbuvir and ribavirin in genotype 3 hepatitis C patients with advanced fibrosis or cirrhosis, for treatment durations of 12 and 16 weeks. The results show that 100% of patients in the advanced fibrosis cohort achieved sustained virologic response (SVR12) in both the 12- and 16-week arms of the study. SVR12 rates were 83% and 89% in patients with cirrhosis in the 12- and 16-week arms, respectively. The combination regimen had no discontinuations due to adverse events and relapse occurred in four patients (two in the 16-week and two in the 12-week arm). There was one death (12-week arm; not treatment-related) and no virologic breakthroughs. Results were presented at The Liver Meeting 2015, the annual meeting of The American Association for the Study of Liver Diseases in San Francisco, California.

Eliquis

In December, the company and its partner, Pfizer, Inc., announced results from a post-hoc subanalysis of the Phase 3 AMPLIFY trial. Results demonstrated that Eliquis was comparable to conventional therapy (subcutaneous enoxaparin overlapped and followed by oral warfarin dose-adjusted to an international normalized ratio of 2.0 to 3.0) in recurrent venous thromboembolism (VTE) and VTE-related death. There was significantly less major bleeding during the first 7, 21 and 90 days after starting treatment. The data were published in Thrombosis and Haemostasis.

ADCETRIS is a trademark of Seattle Genetics, Inc.
Revlimid is a trademark of Celgene Corporation.

BUSINESS DEVELOPMENT UPDATE

In December, the company announced it has entered into agreements with ViiV Healthcare, a global HIV company, to divest its pipeline of investigational HIV medicines including an attachment inhibitor (BMS-663068), currently being investigated in Phase 3 as a therapeutic option for heavily treatment-experienced patients, and a maturation inhibitor (BMS-955176) currently being investigated in Phase 2b development for treatment-naïve and treatment-experienced patients. These transactions are consistent with the evolution of the company’s strategic focus, including the decision announced in June to discontinue its discovery efforts in virology.

In December, the company announced a new research collaboration with the Department of Chemistry at Princeton University that includes the establishment of the Center for Molecular Synthesis (BMS-CMS). The agreement creates opportunities for scientists at Princeton University and the company to collaborate on top-flight synthetic chemistry research, leveraging the two sites’ close proximity to foster a robust exchange of scientific ideas. Research projects will investigate areas of mutual interest and benefit, using the expertise developed in the laboratories of the Princeton faculty to conduct frontier science within the pharmaceutical industry. Over the next five years, the Center will also fund a select group of research fellows each year.

In November, the company announced a definitive agreement to acquire all of the issued and outstanding capital stock of Cardioxyl Pharmaceuticals, Inc., a private biotechnology company focused on the discovery and development of novel therapeutic agents for the treatment of cardiovascular disease. The company completed the acquisition in December. The acquisition gives the company full rights to Cardioxyl’s lead asset CXL-1427, a novel nitroxyl (HNO) donor (prodrug) in Phase 2 clinical development as an intravenous treatment for acute decompensated heart failure.

In November, the company completed a previously announced agreement with Five Prime Therapeutics, Inc. for an exclusive worldwide license and collaboration agreement for the development and commercialization of Five Prime’s colony stimulating factor 1 receptor (CSF1R) antibody program, including FPA008, which is in Phase 1 development for immunology and oncology indications.

The company announced several collaborations as part of the Immuno-Oncology Rare Population Malignancy (I-O RPM) program in the U.S.:

In December, the company announced an agreement with the David Geffen School of Medicine at UCLA to conduct a range of early phase clinical studies. The company will fund positions within UCLA’s fellowship program in the UCLA Division of Hematology/Oncology.

In December, the company announced an agreement with The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute to conduct a range of early phase clinical studies. The company will fund training positions within the Hematology and Medical Oncology fellowship programs of the Ohio State University College of Medicine, Department of Internal Medicine.

In November, the company announced an agreement with The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins to conduct a range of early phase clinical studies. The company will also fund positions within The Johns Hopkins University School of Medicine fellowship program.

2016 FINANCIAL GUIDANCE

Bristol-Myers Squibb is setting its 2016 GAAP and non-GAAP EPS guidance range at $2.30 – $2.40. Both GAAP and non-GAAP guidance assume current exchange rates. Key 2016 non-GAAP guidance assumptions include:

Worldwide revenues increasing in the mid-single digit range.

Full-year gross margin as a percentage of revenues to be approximately 75% – 76%.

Marketing, sales and administrative expenses decreasing in the mid-single digit range.

Research and development expenses increasing in the high-single digit range.

An effective tax rate between 21% and 22%.

The financial guidance for 2016 excludes the impact of any potential future strategic acquisitions and divestitures, and any specified items that have not yet been identified and quantified. The non-GAAP 2016 guidance also excludes other specified items as discussed under "Use of Non-GAAP Financial Information." Details reconciling adjusted non-GAAP amounts with the amounts reflecting specified items are provided in supplemental materials available on the company’s website.

Use of Non-GAAP Financial Information

This press release contains non-GAAP financial measures, including non-GAAP earnings and related earnings per share information. These measures are adjusted to exclude certain costs, expenses, significant gains and losses and other specified items. Among the items in GAAP measures but excluded for purposes of determining adjusted earnings and other adjusted measures are: restructuring and other exit costs; accelerated depreciation charges; IPRD and asset impairments; charges and recoveries relating to significant legal proceedings; upfront, milestone and other payments for in-licensing or acquisition of investigational compounds that have not achieved regulatory approval which are immediately expensed; pension settlement charges; significant tax events and additional charges related to the Branded Prescription Drug Fee. This information is intended to enhance an investor’s overall understanding of the company’s past financial performance and prospects for the future. Non-GAAP financial measures provide the company and its investors with an indication of the company’s baseline performance before items that are considered by the company not to be reflective of the company’s ongoing results. The company uses non-GAAP gross profit, non-GAAP marketing, selling and administrative expense, non-GAAP research and development expense, and non-GAAP other income and expense measures to set internal budgets, manage costs, allocate resources, and plan and forecast future periods. Non-GAAP effective tax rate measures are primarily used to plan and forecast future periods. Non-GAAP earnings and earnings per share measures are primary indicators the company uses as a basis for evaluating company performance, setting incentive compensation targets, and planning and forecasting of future periods. This information is not intended to be considered in isolation or as a substitute for financial measures prepared in accordance with GAAP.

Statement on Cautionary Factors

This press release contains certain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, statements relating to goals, plans and projections regarding the company’s financial position, results of operations, market position, product development and business strategy. These statements may be identified by the fact that they use words such as "anticipate", "estimates", "should", "expect", "guidance", "project", "intend", "plan", "believe" and other words and terms of similar meaning in connection with any discussion of future operating or financial performance. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. These factors include, among other things, effects of the continuing implementation of governmental laws and regulations related to Medicare, Medicaid, Medicaid managed care organizations and entities under the Public Health Service 340B program, pharmaceutical rebates and reimbursement, market factors, competitive product development and approvals, pricing controls and pressures (including changes in rules and practices of managed care groups and institutional and governmental purchasers), economic conditions such as interest rate and currency exchange rate fluctuations, judicial decisions, claims and concerns that may arise regarding the safety and efficacy of in-line products and product candidates, changes to wholesaler inventory levels, variability in data provided by third parties, changes in, and interpretation of, governmental regulations and legislation affecting domestic or foreign operations, including tax obligations, changes to business or tax planning strategies, difficulties and delays in product development, manufacturing or sales including any potential future recalls, patent positions and the ultimate outcome of any litigation matter. These factors also include the company’s ability to execute successfully its strategic plans, including its business development strategy, the expiration of patents or data protection on certain products, including assumptions about the company’s ability to retain patent exclusivity of certain products, and the impact and result of governmental investigations. There can be no guarantees with respect to pipeline products that future clinical studies will support the data described in this release, that the compounds will receive necessary regulatory approvals, or that they will prove to be commercially successful; nor are there guarantees that regulatory approvals will be sought, or sought within currently expected timeframes, or that contractual milestones will be achieved. For further details and a discussion of these and other risks and uncertainties, see the company’s periodic reports, including the annual report on Form 10-K, quarterly reports on Form 10-Q and current reports on Form 8-K, filed with or furnished to the Securities and Exchange Commission. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Lynparza™ (olaparib) granted Breakthrough Therapy designation by US FDA for treatment of BRCA1/2 or ATM gene mutated metastatic Castration Resistant Prostate Cancer

On January 28, 2016 AstraZeneca reported that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy designation (BTD) for the oral poly ADP-ribose polymerase (PARP) inhibitor Lynparza (olaparib), for the monotherapy treatment of BRCA1/2 or ATM gene mutated metastatic Castration Resistant Prostate Cancer (mCRPC) in patients who have received a prior taxane-based chemotherapy and at least one newer hormonal agent (abiraterone or enzalutamide) (Press release, AstraZeneca, 28 1/, 2016, View Source [SID:1234508875]).

The FDA criteria for BTD require preliminary clinical evidence that demonstrates a drug may have substantial improvement on at least one clinically significant endpoint over available therapy. The decision to assign a BTD for Lynparza is based on the results of the TOPARP-A Phase II trial, which found that Lynparza (olaparib) monotherapy in mCPRPC may offer substantial improvement over available therapies for the treatment of the biomarker-selected population with this serious and life-threatening condition. The TOPARP-A Phase II trial was presented at AACR (Free AACR Whitepaper) 2015 and published in the New England Journal of Medicine in October 2015.i It showed that men with prostate cancer with defective DNA damage repair mechanisms responded to Lynparza (olaparib).

The Breakthrough Therapy designation for Lynparza in this patient population means the FDA will expedite review of submission data within 60 days of receipt.
Antoine Yver, Head of Oncology, Global Medicines Development at AstraZeneca, said: "More than 27,000 men died of prostate cancer last year in the US alone. The Breakthrough Therapy designation for Lynparza is encouraging news for patients, and their families, as there are currently very limited treatment options for metastatic Castration Resistant Prostate Cancer. We will work closely with the FDA to introduce Lynparza as a new treatment option as soon as possible."

Once prostate cancer has progressed to mCPRPC, treatment focuses on extending life, delaying disease progression, and improving symptoms and quality of life. Overall survival time for patients treated with chemotherapy and newer hormonal agents is 10 months.ii There are also no approved therapies for third line and above (3L+) mCRPC patients, and no targeted therapies are available for mCRPC patients with somatic or germline mutations in BRCA1, BRCA2 or ATM.

Lynparza (olaparib) is an innovative, first-in-class oral poly ADP-ribose polymerase (PARP) inhibitor that exploits tumour DNA repair pathway deficiencies to preferentially kill cancer cells. This mode of action gives olaparib the potential for activity in a range of tumour types with DNA repair deficiencies.

Lynparza has been approved by regulatory authorities in 40 countries for the maintenance treatment of women with BRCA-mutated ovarian cancer. AstraZeneca is investigating the potential of olaparib in other PARP dependent tumours. Phase III studies in gastric cancer, pancreatic cancer and adjuvant and metastatic BRCAm breast cancers are underway, with further studies planned.

NOTES TO EDITORS

About prostate cancer
In 2015, 27,540 US men died of prostate cancer.iii Based on the Global Burden of Disease Cancer Collaboration, there were 1.4 million incidents of prostate cancer and 293,000 deaths worldwide for the year 2013. Prostate cancer caused 4.8 million disability-adjusted life-years globally in 2013, with 57% occurring in developed countries and 43% occurring in developing countries.iv