On January 29, 2016 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that its U.S. subsidiary Eisai Inc. has received approval from the U.S. Food and Drug Administration (FDA) of its in-house developed anticancer agent Halaven (eribulin mesylate) for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen (Press release, Eisai, JAN 29, 2016, View Source [SID:1234508906]). Halaven is the first and only single agent to demonstrate an overall survival (OS) benefit in a Phase III trial in patients with advanced or recurrent and metastatic soft tissue sarcoma (leiomyosarcoma or liposarcoma). Following approval for use in the treatment of metastatic breast cancer in the United States, this marks the second indication for which Halaven has been approved by the FDA based on a statistically significant extension of OS.

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This approval was based on the results from a multicenter, open-label, randomized Phase III study (Study 309) comparing the efficacy and safety of Halaven versus dacarbazine in 452 patients (aged 18 or over) with locally advanced or recurrent and metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma) who had disease progression following standard therapies which must have included an anthracycline and at least one other additional regimen.

Halaven demonstrated a statistically significant extension in the study’s primary endpoint of OS over the comparator treatment dacarbazine (Halaven median OS: 13.5 months vs dacarbazine median OS: 11.5 months; Hazard Ratio (HR) 0.768 [95% CI=0.618-0.954], p=0.017).1
For patients with liposarcoma, Halaven demonstrated a significant improvement in OS over dacarbazine (Halaven, n=71, median OS: 15.6 months vs dacarbazine, n=72, median OS: 8.4 months; HR 0.51 [95% CI=0.35-0.75]).2 Additionally, in the study’s secondary endpoint of progression-free survival (PFS), patients treated with Halaven experienced an improvement in PFS over dacarbazine (Halaven median PFS: 2.9 months vs dacarbazine median PFS: 1.7 months; HR 0.52 [95% CI=0.35-0.78]).2

The most common adverse reactions (incidence greater than or equal to 25%) in study patients with liposarcoma and leiomyosarcoma treated with Halaven were fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain and pyrexia, which was consistent with the known side-effect profile of Halaven.2 The most common (incidence greater than or equal to 5%) Grade 3-4 laboratory abnormalities reported in patients receiving Halaven were neutropenia, hypokalemia, and hypocalcemia. The most common serious adverse reactions reported in patients receiving Halaven were neutropenia (4.9%) and pyrexia (4.5%).2

Soft tissue sarcoma is a collective term for a diverse group of malignant tumors that occur throughout the soft tissues (fat, muscle, nerves, fibrous tissues and blood vessels) in the body. Approximately 12,000 patients in the United States are diagnosed with soft tissue sarcoma each year, and liposarcoma is one of the most common forms of soft tissue sarcoma. As outcomes are poor for patients with advanced disease, it remains a disease with significant unmet medical need.

Applications seeking approval of Halaven for use in the treatment of soft tissue sarcoma have been submitted in Europe and Japan. Meanwhile, the agent has been designated as an orphan drug for the treatment of soft tissue sarcoma in the United States and Japan.

Halaven is a halichondrin class microtubule dynamics inhibitor with a distinct binding profile.2 In addition, recent non-clinical studies showed that Halaven is associated with increased vascular perfusion and permeability in tumor cores.3 Halaven promotes the epithelial state and decreases the capacity of breast cancer cells to migrate.4 It was first approved in the United States in November 2010 for patients with metastatic breast cancer who have received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. Halaven is currently approved for use in the treatment of breast cancer in approximately 60 countries including Japan and countries in Europe, the Americas and Asia.

Through this additional approval, Eisai remains committed to providing further clinical evidence for Halaven aimed at maximizing value of the drug as it seeks to contribute further to addressing the diverse needs of, and increasing the benefits provided to, patients with cancer, their families, and healthcare providers.

< Notes to editors >

1. About Halaven (eribulin mesylate)
Halaven is the first in the halichondrin class of microtubule dynamics inhibitors with a novel mechanism of action. Structurally Halaven is a simplified and synthetically produced version of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. Halaven is believed to work by inhibiting the growth phase of microtubule dynamics which prevents cell division. In addition, recent non-clinical studies showed that Halaven is associated with increased vascular perfusion and permeability in tumor cores.3 Halaven promotes the epithelial state and decreases the capacity of breast cancer cells to migrate.4
Halaven was first approved as a treatment in the United States in November 2010 for patients with metastatic breast cancer who have received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. Halaven is currently approved for use in the treatment of breast cancer in approximately 60 countries worldwide, including Japan and countries in the Europe, Americas and Asia. In Japan, Halaven has been approved to treat inoperable or recurrent breast cancer and was launched in the country in July 2011. Halaven has also been approved in countries in Europe and Asia indicated as a treatment for patients with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting, unless patients were not suitable for these treatments.
Regarding soft tissue sarcoma, Halaven has been approved in the United States for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen, and applications seeking approval for this potential indication have been submitted in Japan and Europe. Meanwhile, Halaven has been designated as an orphan drug for soft-tissue sarcoma in the United States and Japan.

2. About Soft Tissue Sarcoma
Soft tissue sarcoma is a collective term for a diverse group of malignant tumors that occur throughout the soft tissue (fat, muscle, nerves, fibrous tissues and blood vessels) in the body. Approximately 12,000 patients in the United States and 29,000 patients in Europe are diagnosed with soft tissue sarcoma each year. According to a patient survey conducted by Japan’s Ministry of Health, Labour and Welfare, there are approximately 4,000 patients with soft tissue sarcoma in Japan. As the structures where the tumors originate are diverse, there are various types of soft tissue sarcoma, and the most common types include leiomyosarcoma, liposarcoma and malignant fibrous histiocytoma. While treatment of soft tissue sarcoma is focused on curative surgery, if the degree of malignancy is high, treatment then becomes a combination of chemotherapy and radiation therapy. As outcomes are poor for patients with advanced disease, it remains a disease with significant unmet medical need.

3. About Study 309
Conducted primarily in Europe and the United States, Study 309 was a multicenter, open-label, randomized Phase III study comparing the efficacy and safety of Halaven versus dacarbazine in 452 patients (aged 18 or over) with locally advanced or recurrent and metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma) who had disease progression following standard therapies which must have included an anthracycline and at least one other additional regimen. Patients received either Halaven (1.4 mg/m2 administered intravenously on Day 1 and Day 8) or dacarbazine (850–1200 mg/m2 administered intravenously on Day 1) every 21 days until disease progression.
From the results for the study, Halaven demonstrated a statistically significant extension in the study’s primary endpoint of overall survival (OS) over the comparator treatment dacarbazine (Halaven median OS: 13.5 months vs dacarbazine median OS: 11.5 months; Hazard Ratio (HR) 0.768 [95% CI=0.618-0.954], p=0.017).1 Furthermore, in the study’s secondary endpoints, there was no statistically significant difference found between Halaven and dacarbazine in either progression-free survival (PFS) (median PFS: 2.6 months in both arms) or progression-free rate at 12 weeks (PFR12wks) (Halaven PFR12wks: 33% vs dacarbazine PFR12wks: 29%).1
For patients with liposarcoma, Halaven demonstrated a statistically significant improvement in OS over dacarbazine (Halaven, n=71, median OS: 15.6 months vs dacarbazine, n=72, median OS: 8.4 months; HR 0.51 [95% CI=0.35-0.75]).2 Additionally, patients treated with Halaven experienced an improvement in PFS over dacarbazine (Halaven median PFS: 2.9 months vs dacarbazine median PFS: 1.7 months; HR 0.52 [95% CI=0.35-0.78]).2
The most common adverse reactions (incidence greater than or equal to 25%) in study patients with liposarcoma and leiomyosarcoma treated with Halaven were fatigue (62%), nausea (41%), alopecia (35%), constipation (32%), peripheral neuropathy (29%), abdominal pain (29%) and pyrexia (28%), which was consistent with the known side-effect profile of Halaven.2 The most common (incidence greater than or equal to 5%) Grade 3-4 laboratory abnormalities reported in patients receiving Halaven were neutropenia (32% vs. 8.9% in the dacarbazine arm), hypokalemia (5.4% vs. 2.8%) and hypocalcemia (5.0% vs. 1.4%). The most common serious adverse reactions reported in patients receiving Halaven were neutropenia (4.9%) and pyrexia (4.5%).2 The most common adverse reactions resulting in discontinuation of Halaven were fatigue and thrombocytopenia (0.9% each).

On January 29, 2016 ImmunoGen, Inc. (Nasdaq: IMGN), a biotechnology company that develops targeted anticancer therapeutics using its proprietary ADC technology, reported financial results for the three-month period ended December 31, 2015 — the second quarter of the Company’s 2016 fiscal year (Filing, 8-K, ImmunoGen, JAN 29, 2016, View Source [SID:1234508907]). ImmunoGen also provided an update on product programs and reiterated its 2016 fiscal year guidance.

"ImmunoGen is off to a strong start for 2016, with multiple clinical trial initiations underway," commented Daniel Junius, President and CEO. "Of particular importance is the opening of our FORWARD I trial assessing mirvetuximab soravtansine as single-agent therapy for pretreated FRα-positive ovarian cancer, which we believe is the fastest path to registration for this promising ADC. We expect several presentations of mirvetuximab soravtansine data in 2016, including mature results from the 40-patient FRα-positive ovarian cancer Phase 1 cohort."

Mr. Junius continued, "Our partners also are making meaningful progress. Of particular note is Bayer’s initiation of a Phase 2 trial designed to support registration of its anetumab ravtansine product candidate. Roche expects data to be reported from its trial assessing Kadcyla in the neoadjuvant setting this year and — if positive — to bring these to regulatory authorities for potential filing in 2016. A third partner compound is on track to advance into registration testing later this year."

Update on Wholly Owned Product Programs

Mirvetuximab soravtansine — First FRα-targeting ADC is a potential new treatment for ovarian cancer and other FRα-positive solid tumors.

· Assessments as single-agent therapy for pretreated FRα-positive ovarian cancer:

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· Updated Phase 1 findings were presented at the AACR (Free AACR Whitepaper)-NCI-EORTC meeting in November for the dataset reported at ASCO (Free ASCO Whitepaper) in May (abstracts #C47 and #5518, respectively). These included that 35% (7/20) of patients with FRα-positive platinum-resistant disease treated had a confirmed objective response, with most (6/7) responders on mirvetuximab soravtansine for 6 months or longer. This compares with ImmunoGen’s target response rate of 30% or more to advance the ADC as monotherapy. Most of the patients and all of the responders had high or medium FRα levels on their tumors.

· Patient enrollment is open for the Company’s FORWARD I Phase 2 trial, which is designed to support an Accelerated Approval pathway for mirvetuximab soravtansine. FORWARD I is being conducted in partnership with the GOG Foundation, Inc. To qualify for enrollment, patients must have ovarian cancer with high or medium FRα expression that was previously treated with 3 or 4 regimens.

· Patient enrollment was completed in 4Q2015 in the 20-patient Phase 1 expansion cohort requiring biopsies. The Company intends to present initial biomarker data from this assessment at a medical meeting in 2Q2016 in addition to reporting mature data from the 40-patient Phase 1 cohort in this disease at the meeting.

· Assessments as combination therapy for FRα-positive ovarian cancer:

· Encouraging preclinical data with a range of combination regimens were presented at the AACR (Free AACR Whitepaper)-NCI-EORTC meeting (abstract C170).

· In December, patient dosing began in the Phase 1b/2 trial, FORWARD II, assessing mirvetuximab soravtansine in combination with approved anticancer agents.

· Assessments for the treatment of other FRα-positive cancers:

· In 4Q2015, patient enrollment was completed in the 20-patient Phase 1 expansion cohort assessing the ADC for FRα-positive relapsed/refractory endometrial cancer. The Company expects to report findings from this assessment in 2H2016.

· Additional cancer types are being evaluated for FRα expression preclinically.

IMGN529 and coltuximab ravtansine — CD37- and CD19-targeting, respectively, ADCs for diffuse large B-cell lymphoma (DLBCL) and potentially other B-cell malignancies.

· Preclinical findings of strong synergy for IMGN529 used in combination with rituximab were reported at ASH (Free ASH Whitepaper) (abstract #1548) in December.

· Patient enrollment in a Phase 2 trial assessing IMGN529 in combination with rituximab is expected to begin early this year. Enrollment in a Phase 2 trial assessing coltuximab ravtansine in a different combination regimen is expected to begin in 2H2016.

IMGN779 — First CD33-targeting ADC utilizing an IGN cancer-killing agent. IGNs are a

new class of DNA-acting agents invented by ImmunoGen.

· Mechanism of action data were reported at ASH (Free ASH Whitepaper) (abstract #1366).

· ImmunoGen is preparing to initiate Phase 1 testing of IMGN779 for the treatment of acute myeloid leukemia in 1H2016.

Update on Partner Programs

Nine companies are advancing ADCs with ImmunoGen technology. Recent highlights include:

· Patient dosing has begun in Bayer’s global Phase 2 clinical trial designed to support registration of its mesothelin-targeting ADC, anetumab ravtansine. This event triggers a milestone payment to ImmunoGen that will be reflected in the Company’s 3QFY2016 financial results.

· Roche expects data from its KRISTINE trial assessing Kadcyla in the neoadjuvant setting for early HER2-positive breast cancer to be reported this year and, if positive, to bring these to regulatory authorities for potential filing in 2016.

· In December, Takeda took its first license for the exclusive right to develop ADCs to an undisclosed target using ImmunoGen technology.

· Also in December, CytomX announced it is advancing a novel anticancer agent targeting CD166 using its ProbodyTM technology and ImmunoGen’s ADC technology under a strategic collaboration established between the companies in early 2014.

Financial Results

For the Company’s quarter ended December 31, 2015 (2QFY2016), ImmunoGen reported a net loss of $(33.2) million, or $(0.38) per basic and diluted share, compared to net income of $13.6 million, or $0.16 per basic and diluted share, for the same quarter last year (2QFY2015).

Revenues for 2QFY2016 were $18.0 million, compared to $48.3 million for 2QFY2015. The current period includes $8.6 million of amortization of upfront fees previously received from Takeda and the prior year period includes $41.4 million of amortization of upfront fees previously received from Novartis and Lilly. The fees are recognized in their respective quarters due to the partner taking one or more licenses in the quarter. License and milestone fees for 2QFY2016 also include a $2 million milestone earned from Sanofi with the advancement of SAR428926 into clinical testing. Revenues in 2QFY2016 include $6.3 million of non-cash royalty revenues and $0.2 million of cash royalty revenues on Roche sales of Kadcyla for the three-months ended September 30, 2015, compared with $4.6 million in cash royalty revenues for the prior year period.

Operating expenses in 2QFY2016 were $46.3 million, compared to $34.5 million in 2QFY2015. Operating expenses in 2QFY2016 include research and development expenses of $38.2 million, compared to $27.6 million in 2QFY2015. This change is primarily due to increased third-party costs related to the advancement of our wholly owned product candidates, increased clinical trial costs, primarily related to our expansion of the mirvetuximab soravtansine development program, and increased

personnel expenses, principally due to recent hiring. Operating expenses include general and administrative expenses of $8.1 million in 2QFY2016, compared to $6.9 million in 2QFY2015. This increase is primarily due to increased personnel expenses and professional services.

ImmunoGen had approximately $212.3 million in cash and cash equivalents as of December 31, 2015, compared with $278.1 million as of June 30, 2015, and had no debt outstanding in either period. Cash used in operations was $63.0 million in the first six months of FY2016, compared with $34.4 million in the same period in FY2015. Capital expenditures were $7.6 million and $2.6 million for the first six months of FY2016 and FY2015, respectively.

Financial Guidance for Fiscal Year 2016

ImmunoGen’s financial guidance remains unchanged from that issued in July 2015. ImmunoGen expects: its revenues to be between $70 million and $80 million; its operating expenses to be between $175 million and $180 million; its net loss to be between $120 million and $125 million; its cash used in operations to be between $100 million and $105 million; and its capital expenditures to be between $13 million and $15 million. Cash and cash equivalents at June 30, 2016 are anticipated to be between $165 million and $170 million.

On January 29, 2016 Spectrum Pharmaceuticals, Inc. (NasdaqGS: SPPI), a biotechnology company with fully integrated commercial and drug development operations and a primary focus in Hematology and Oncology, reported the Company has initiated the planned registrational trial for SPI-2012 (eflapegrastim), its novel, long-acting G-CSF (Press release, Spectrum Pharmaceuticals, JAN 29, 2016, View Source [SID:1234508908]). This trial will evaluate the safety and efficacy of SPI-2012 as a treatment for chemotherapy-induced neutropenia in patients with breast cancer, and will serve as the basis for the Biologics License Application (BLA) filing.

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"The initiation of the registration trial for SPI-2012 is a significant milestone in the history of our company," said Rajesh C. Shrotriya, MD, Chairman and Chief Executive Officer of Spectrum Pharmaceuticals. "Revenues from our current marketed drugs have helped us invest in this exciting technology that opens the door for us to a blockbuster oncology market. In parallel, Spectrum has built a strong commercial infrastructure with specialized expertise in this indication that positions us well to aggressively compete in this market."

"I am excited to be the lead investigator for this important study, and about the potency and safety of SPI-2012 as demonstrated in Phase 2," said Lee S. Schwartzberg, M.D., FACP Professor of Medicine and Division Chief, Hematology Oncology, The University of Tennessee Health Science Center, and Executive Director, UT/West Cancer Center. "The LAPSCOVERY technology confers long-acting properties and increased bone marrow uptake through decreased renal and vascular clearance, as well as Fc-mediated transport of G-CSF. We look forward to a successfully conducted Phase 3 trial of SPI-2012. I believe this novel biologic drug, if approved, would be a very valuable addition to our supportive care armamentarium for cancer patients receiving myelosuppressive cytotoxic chemotherapy."

"SPI-2012 is a third generation agent for the treatment of neutropenia that has shown promising results in Phase 2 trials," said, Jeffrey L. Vacirca, M.D., FACP CEO, Managing Partner & Chief of Clinical Research at North Shore Hematology/Oncology Associates and Vice-President, Community Oncology Alliance. "In the Phase 2 trial, the duration of severe neutropenia was equivalent to pegfilgrastim at the medium dose and superior at the high dose. No new or significant dose-related toxicities have been observed in over 230 patients who have been treated with SPI-2012, and the incidence of adverse events has been similar to pegfilgrastim."

In accordance with the SPA, this registrational, Phase 3 or ADVANCE study (RAnDomized Trial of SPI-2012 Versus Pegfilgrastim in the Management of Chemotherapy Induced Neutropenia in Breast CANCEr Patients Receiving Docetaxel and Cyclophosphamide) is a multicenter, randomized, active controlled trial that will enroll 580 newly diagnosed early-stage breast cancer patients, who will receive adjuvant or neoadjuvant chemotherapy every 21 days. Adjuvant chemotherapy is treatment given after primary surgical therapy to kill any remaining cancer cells and increase the chance of long-term disease-free survival; neoadjuvant chemotherapy is the administration of cytotoxic agents before surgical resection in early-stage breast cancer to shrink the tumor and potentially allow for breast-conserving surgery. SPI-2012 will be administered subcutaneously as a fixed dose equivalent to 3.6 mg of GCSF, which was selected based on the robust pharmacological and pharmacodynamic data from Phase 2. The primary study endpoint is the Duration of Severe Neutropenia (Absolute Neutrophil Counts [ANC] < 0.5×109/L) in Cycle 1 of chemotherapy, based on central laboratory assessment of ANC over the 21 day cycle. Secondary endpoints include the incidence of neutropenic complications, incidence of Febrile Neutropenia, Relative Dose Intensity, and safety.

About Special Protocol Assessments

A Special Protocol Assessment is a written agreement between a Sponsor and the U.S. Food and Drug Administration on the design, execution and analysis for a clinical trial that may form the basis of a new Biologics License Application or BLA. Final marketing approval depends upon the efficacy results, safety profile and an evaluation of the risk/benefit of treatment demonstrated in the Phase 3 clinical program.

About Breast Cancer

According to the American Cancer Society (ACS), breast cancer is the second most common form of cancer in women after skin cancer, and the second highest cause of female cancer deaths after lung cancer. Unfortunately, it is estimated that about 1 in 8 (12%) of women in the US will develop invasive breast cancer during their lifetime. In 2015 in the United States (US), an estimated 231,840 new cases of invasive breast cancer and 60,290 additional cases of in situ breast cancer will be diagnosed, and approximately 40,290 US women are expected to die from breast cancer. In addition, ~2,350 men are also expected to be diagnosed with breast cancer in 2015 with an estimated 440 deaths.

On January 29, 2016, in Tokyo, Japan (January 28, 2016, in San Francisco, CA), Medivation, Inc.’s collaboration partner Astellas Pharma Inc. (Astellas), reported its financial results for the quarter ended December 31, 2015 (Filing, 8-K, Medivation, JAN 29, 2016, View Source [SID:1234508921]).

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Astellas reported, among other things, that U.S. net sales of XTANDI (enzalutamide) capsules were $315.9 million for the quarter ended December 31, 2015 (Medivation’s fourth quarter), an increase of $85.7 million or 37% over the prior year quarter. The Astellas-reported net sales of $315.9 million increased by approximately one percent above the reported net sales of $313.0 million in the quarter ended September 30, 2015. Net sales for the quarter ended December 31 included an unfavorable adjustment of $2.6 million related to changes in Astellas’ estimate of prior period gross-to-net deductions against gross sales and an increase in channel partner inventory of just over one-half week of supply. As previously disclosed, the reported net sales of $313.0 million for the September quarter included a favorable adjustment of $17.9 million related to changes in Astellas’ estimate of prior period gross-to-net deductions against gross sales. Based on information provided by Astellas, the estimated growth in prescription demand from the quarter ended September 30, 2015 to the quarter ended December 31, 2015 was a low- to mid- single digit percentage. For the year ended December 31, 2015, U.S. net sales of XTANDI, as reported by Astellas, were $1.151 billion, an increase of $471.5 million or 69% over the prior year.

In its release, Astellas also reported net sales of XTANDI outside of the U.S. for the quarter ended December 31, 2015, expressed in various currencies. Medivation estimates such sales (expressed in U.S. dollars) were approximately $231 million for the quarter, which represents an increase of approximately 83% over the quarter ended December 31, 2014 and 13% over the quarter ended September 30, 2015. Medivation estimates net sales of XTANDI outside of the U.S. for the full year ended December 31, 2015 were approximately $757 million, an increase of approximately 99% over net sales for the year ended December 31, 2014. Fluctuating currency exchange rates reduced such estimated 2015 ex-U.S. net sales at the Astellas level, as expressed in U.S. dollars, by approximately 10% for the quarter and 14% for the year compared with the respective 2014 periods.

Based on the above, Medivation estimates worldwide net sales of XTANDI at the Astellas level were approximately $547 million for the quarter ended December 31, 2015 and $1.908 billion for the year ended December 31, 2015. Medivation earned the final sales milestone of $175 million under the collaboration with Astellas in the quarter ended December 31, 2015, based upon worldwide net sales exceeding $1.6 billion in the calendar year.

Medivation plans to report its own financial results for the quarter and year ended December 31, 2015, on February 25, 2016.

The information in this Item 7.01 is being furnished and shall not be deemed filed for purposes of Section 18 of the Exchange Act, or otherwise subject to the liability of that section, nor shall such information be deemed to be incorporated by reference in any registration statement or other document filed under the Securities Act of 1933, as amended, or the Exchange Act, except as otherwise stated in such filing.

On January 28, 2016 Amgen (NASDAQ:AMGN) reported financial results for the fourth quarter and full year of 2015 (Press release, Amgen, JAN 28, 2016, View Source;p=RssLanding&cat=news&id=2133283 [SID:1234508901]). Key results include:

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For the fourth quarter, total revenues increased 4 percent to $5,536 million, with 3 percent product sales growth driven by Enbrel (etanercept), Sensipar (cinacalcet), Prolia (denosumab), Kyprolis (carfilzomib) and XGEVA (denosumab). Adjusted operating income grew 16 percent to $2,366 million and adjusted EPS grew 21 percent to $2.61.

For the full year, total revenues increased 8 percent to $21,662 million, with 8 percent product sales growth. Adjusted operating income grew 19 percent to $10,052 million and adjusted EPS grew 19 percent to $10.38.

2015 adjusted operating margin improved by 4 percentage points to 48 percent.

GAAP EPS were $2.37 in the fourth quarter compared to $1.68 a year ago and $9.06 for the full year compared to $6.70 in 2014. GAAP operating income was $2,033 million in the fourth quarter compared to $1,459 million a year ago and $8,470 million for the full year compared to $6,191 million in 2014. 2014 was negatively impacted by charges for the restructuring plan announced in the third quarter of 2014.

Free cash flow for the full year was $8.5 billion compared to $7.8 billion in 2014 driven by higher revenues and higher operating income.

"2015 was an exceptional year for Amgen with six innovative new launches, strong financial performance, continued pipeline advances and improved operating margins driven by our transformation efforts," said Robert A. Bradway, chairman and chief executive officer. "We remain on track to meet or exceed our 2018 commitments and deliver value for patients and shareholders."

References in this release to "adjusted" measures, measures presented "on an adjusted basis" or to free cash flow refer to non-GAAP financial measures. These adjustments and other items are presented on the attached reconciliations.

Product Sales Performance

Total product sales increased 3 percent for the fourth quarter of 2015 versus the fourth quarter of 2014. The increase was driven primarily by ENBREL, Sensipar, Prolia, Kyprolis and XGEVA. Product sales increased 8 percent for the full year.

ENBREL sales increased 8 percent year-over-year for the fourth quarter driven by net selling price, offset partially by the impact from inventory changes and competition. Sales increased 14 percent for the full year driven by net selling price, offset partially by the impact from competition.

Neulasta (pegfilgrastim) sales decreased 2 percent year-over-year for the fourth quarter driven by lower unit demand and unfavorable changes in foreign exchange rates, offset partially by net selling price. Sales increased 3 percent for the full year driven by net selling price, offset partially by unfavorable changes in foreign exchange rates.

Aranesp (darbepoetin alfa) sales increased 4 percent year-over-year for the fourth quarter and 1 percent for the full year. Unit demand grew in the United States (U.S.) as dialysis customers shifted some purchases from EPOGEN (epoetin alfa) to Aranesp.

Unit demand growth was offset partially by unfavorable changes in foreign exchange rates and net selling price.

Sensipar/Mimpara sales increased 21 percent year-over-year for the fourth quarter and 22 percent for the full year driven by net selling price and higher unit demand.

Prolia sales increased 21 percent year-over-year for the fourth quarter and 27 percent for the full year driven by higher unit demand.

XGEVA sales increased 10 percent year-over-year for the fourth quarter and 15 percent for the full year driven primarily by higher unit demand.

EPOGEN sales decreased 37 percent year-over-year for the fourth quarter and 9 percent for the full year driven by the impact of competition and, to a lesser extent, the shift in U.S. dialysis customer purchases to Aranesp.

NEUPOGEN (filgrastim) sales decreased 4 percent year-over-year for the fourth quarter driven by the impact of competition in the U.S. and unfavorable changes in foreign exchange rates, offset partially by favorable changes in accounting estimates. Sales decreased 9 percent for the full year driven by the impact of competition in the U.S.

Kyprolis sales increased 63 percent year-over-year for the fourth quarter and 55 percent for the full year driven by higher unit demand.

Nplate (romiplostim) sales increased 15 percent year-over-year for the fourth quarter and 12 percent for the full year driven by higher unit demand.

Vectibix (panitumumab) sales increased 2 percent year-over-year for the fourth quarter and 9 percent for the full year driven by higher unit demand, offset partially by unfavorable changes in foreign exchange rates.
Product Sales Detail by Product and Geographic Region

Operating Expense, Operating Margin and Tax Rate Analysis, on an Adjusted Basis

Operating Expenses decreased 4 percent year-over-year in the fourth quarter of 2015 and remained flat for the full year. Changes in foreign exchange rates reduced operating expenses by 2 percent in the fourth quarter and 3 percent for the full year.

Cost of Sales margin improved by 1.6 percentage points year-over-year in the fourth quarter of 2015 and 1.3 percentage points for the full year driven primarily by manufacturing efficiencies, higher net selling price and lower royalties.

Research & Development (R&D) expenses decreased 10 percent year-over-year in the fourth quarter of 2015 driven by savings from transformation and process improvement efforts, as well as a $60 million upfront payment in the fourth quarter of 2014 related to the Company’s cancer immunotherapy collaboration with Kite Pharma. For the full year, R&D expenses decreased 5 percent driven primarily by savings from transformation and process improvement efforts, offset partially by increased support for launch products.

Selling, General & Administrative (SG&A) expenses increased 3 percent year-over-year in the fourth quarter of 2015 and 6 percent for the full year driven primarily by investments in new product launches, offset partially by savings from transformation and process improvement efforts.

Operating Margin improved by 5 percentage points year-over-year in the fourth quarter of 2015 and 4 percentage points for the full year.

Adjusted Tax Rate for the fourth quarter of 2015 increased 1.4 percentage points year-over-year driven primarily by a lower benefit from the federal R&D tax credit. The full year adjusted tax rate increased 1.9 percentage points driven primarily by changes in the geographic mix of earnings.

The Company generated $1.9 billion of free cash flow in the fourth quarter of 2015 versus $2.2 billion in the fourth quarter of 2014. For the full year, free cash flow was $8.5 billion compared to $7.8 billion in 2014 driven by higher revenues and higher operating income.

The Company’s first quarter 2016 dividend of $1.00 per share declared on Dec. 15, 2015, will be paid on March 8, 2016, to all stockholders of record as of Feb. 16, 2016.

During the fourth quarter, the Company repurchased 1.2 million shares of common stock at a total cost of $184 million. For the full year, the Company repurchased 12 million shares of common stock at a total cost of $1.85 billion. At the end of 2015, the Company had $4.9 billion remaining under its stock repurchase authorization.

2016 Guidance

For the full year 2016, the Company now expects:

Total revenues in the range of $22.0 billion to $22.5 billion and adjusted EPS in the range of $10.60 to $11.00. Previously, the Company expected total revenues in the range of $21.7 billion to $22.3 billion and adjusted EPS in the range of $10.35 to $10.75.
Adjusted tax rate to be in the range of 19.5 percent to 20.5 percent, which includes the benefit of the federal R&D tax credit.
Capital expenditures to be approximately $700 million.

The Company provided the following updates on selected product and pipeline programs:

Repatha

In January 2016, Repatha was approved in Japan for the treatment of patients with familial hypercholesterolemia (FH) or hypercholesterolemia who have high risk of cardiovascular events and do not adequately respond to HMG-CoA reductase inhibitors (statins).

Kyprolis

In November, the European Medicines Agency (EMA) approved the Marketing Authorization Application (MAA) for Kyprolis in combination for the treatment of relapsed multiple myeloma based on data from the Phase 3 ASPIRE study.

In December, a Variation to the MAA was submitted to the EMA to expand the indication for Kyprolis in relapsed multiple myeloma based on data from the Phase 3 ENDEAVOR study.

In January 2016, the U.S. Food and Drug Administration (FDA) approved the supplemental New Drug Application for Kyprolis in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy. The FDA also approved Kyprolis as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy. This FDA decision converts to full approval the initial accelerated approval Kyprolis received in July 2012 as a single agent.

BLINCYTO (blinatumomab)

In November, the EMA approved the MAA for BLINCYTO for the treatment of Philadelphia chromosome-negative relapsed or refractory B-precursor acute lymphoblastic leukemia.
IMLYGIC

In December, the EMA approved the MAA for IMLYGIC for the treatment of adults with unresectable melanoma that is regionally or distantly metastatic (Stage IIIB, IIIC and IVM1a) with no bone, brain, lung or other visceral disease.
XGEVA

Data from the event driven Phase 3 study for the prevention of skeletal-related events in patients with multiple myeloma is expected in Q4 2016.

Romosozumab

Data from the Phase 3 registrational study in women with postmenopausal osteoporosis is expected in Q1 2016.
AMG 334

Data from the Phase 2b study in patients with chronic migraine is expected in H2 2016.
Biosimilars

In January 2016, the FDA accepted for review Amgen’s Biologics License Application for ABP 501, a biosimilar candidate to Humira (adalimumab), and set a Biosimilar User Fee Act target action date of Sept. 25, 2016.

In December, a MAA was submitted to the EMA for ABP 501.

Non-GAAP Financial Measures
In this news release, management has presented its operating results for the fourth quarters and full years of 2015 and 2014 in accordance with U.S. Generally Accepted Accounting Principles (GAAP) and on an adjusted (or non-GAAP) basis. In addition, management has presented its full year 2016 EPS and tax rate guidance in accordance with GAAP and on an adjusted (or non-GAAP) basis. These non-GAAP financial measures are computed by excluding certain items related to acquisitions, restructuring and certain other items from the related GAAP financial measures. Management has also presented Free Cash Flow (FCF), which is a non-GAAP financial measure, for the fourth quarters and full years of 2015 and 2014. FCF is computed by subtracting capital expenditures from operating cash flow, each as determined in accordance with GAAP. Reconciliations for these non-GAAP financial measures to the most directly comparable GAAP financial measures are included in the news release.

The Company believes that its presentation of non-GAAP financial measures provides useful supplementary information to and facilitates additional analysis by investors. The Company uses certain non-GAAP financial measures to enhance an investor’s overall understanding of the financial performance and prospects for the future of the Company’s core business activities by facilitating comparisons of results of core business operations among current, past and future periods. In addition, the Company believes that excluding the non-cash amortization of intangible assets, including developed product technology rights, acquired in business combinations treats those assets as if the Company had developed them internally in the past, and thus provides a supplemental measure of profitability in which the Company’s acquired intellectual property is treated in a comparable manner to its internally developed intellectual property. The Company believes that FCF provides a further measure of the Company’s liquidity.

The Company uses the non-GAAP financial measures set forth in the news release in connection with its own budgeting and financial planning. The non-GAAP financial measures are in addition to, not a substitute for, or superior to, measures of financial performance prepared in accordance with GAAP.