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Amgen’s 2015 Revenues Increased 8 Percent To $21.7 Billion And Adjusted Earnings Per Share (EPS) Increased 19 Percent To $10.38

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.

8-K – Current report

On January 28, 2016 Eagle Pharmaceuticals, Inc. (Nasdaq: EGRX) reported that Teva Pharmaceuticals has commenced shipment of BENDEKA, (bendamustine hydrochloride) injection, a liquid, low-volume (50 mL) and short-time 10-minute infusion formulation of bendamustine (Filing, 8-K, Eagle Pharmaceuticals, JAN 28, 2016, View Source [SID:1234508898]). BENDEKA is approved for the treatment of patients with chronic lymphocytic leukemia (CLL) and for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Efficacy in CLL relative to first-line therapies other than chlorambucil has not been established.

According to Paul Rittman, Senior Vice President and General Manager, Teva Oncology, "With the launch of BENDEKA, Teva furthers our commitment to providing treatment options for patients with these rare forms of cancer. We believe BENDEKA represents an important benefit to both patients and healthcare providers, and are pleased it is now available. Based on the product profile, we expect BENDEKA to replace TREANDA liquid."

Under a February 2015 exclusive license agreement for BENDEKA, Teva is responsible for all U.S. commercial activities for the product including promotion and distribution.

The information furnished pursuant to Item 7.01 of this current report shall not be deemed to be "filed" for the purposes of Section 18 of the Securities Exchange Act of 1934, as amended. As such, this information shall not be incorporated by reference into any of the Company’s reports or other filings made with the Securities and Exchange Commission. The furnishing of the information in this current report is not intended to, and does not, constitute a determination or admission by the Company that the information in this current report is material or complete, or that investors should consider this information before making an investment decision with respect to any security of the Company.

Sophiris Bio Reports Encouraging Preliminary Data from Phase 2a Proof of Concept Study in Localized Prostate Cancer

On January 28, 2016 Sophiris Bio Inc. (NASDAQ: SPHS) (the "Company" or "Sophiris"), a biopharmaceutical company developing PRX302 (topsalysin) for the treatment of urological diseases, reported the biopsy data at 6 months for the first seven patients to complete the Phase 2a proof-of-concept study in localized prostate cancer (Press release, Sophiris Bio, JAN 28, 2016, View Source [SID:1234508896]).

A review of the biopsy data from the first seven men to complete the study showed that four patients experienced a response to treatment: One patient experienced complete ablation of the tumor where no evidence of the treated tumor remained on a targeted biopsy at 6 months; three patients experienced either a reduction in the maximum cancer core length or a reduction in Gleason pattern; three patients had no response to treatment.

"This new trial is very exciting — we have promising data showing that topsalysin can ablate cancer cells and we look forward to reviewing the results from the remaining 11 patients as they complete the study. We could be on the cusp of a new class of therapeutics for the focal treatment of localized prostate cancer," stated Professor Mark Emberton, Dean, Faculty of Medical Sciences, University College London and Honorary Consultant Urologist University College London Hospital NHS Foundation Trust.

Dr. Hashim Ahmed, Principal Investigator for the study, Division of Surgery and Interventional Sciences, University College London, said, "Topsalysin could offer a tissue-sparing cancer treatment that carries little in the way of side effects. This treatment has the potential to help men avoid radical treatments such as radiation therapy or complete removal of the prostate."

This one-time administration of topsalysin directly into a pre-identified clinically significant tumor appears to be well tolerated with no serious adverse events and no new safety signals being reported. This is consistent with safety observed in the 365 patients that have been treated with topsalysin in the Company’s BPH program to date.

"The biological activity that we have observed further validates the mechanism of action of topsalysin. We are gaining valuable experience on how we might best optimize both the delivery and dose of topsalysin based on lesion size, and the remaining patients to complete the study will help in that assessment," said Dr. Ahmed.

The ongoing Phase 2a proof of concept study is a single-center, open-label study at University College London, which is well known for the focal treatment of prostate cancer in the UK. In this study, previously obtained multiparametric magnetic resonance images (mpMRIs) of each patient’s prostate tumor lesions are mapped to real-time three-dimensional transrectal ultrasound. These images are used to guide the injection of topsalysin to treat a single, histologically-proven, clinically significant prostate cancer lesion. The primary objective of the study is safety and tolerability, and the key efficacy variable is the change in the treated lesion on targeted biopsy after 6 months. The study is designed to assess whether topsalysin has the potential to provide patients with clinically significant, localized, low to intermediate risk prostate cancer a tissue-sparing cancer treatment that carries little in the way of side effects. A total of 18 patients were enrolled and treated in this study. Sophiris expects to have final data on all patients by the end of the second quarter of 2016.

Webcast scheduled for today at 11:00 a.m. Pacific Time
The Sophiris management team will host a conference call and webcast today, January 28, at 11:00 a.m. Pacific Time to review the topsalysin prostate cancer data as well as the previously announced results of the topsalysin Phase 3 study in BPH. Dr. Hashim Ahmed, University College London and an investigator in the prostate cancer study, and Dr. Marc Gittelman, Director of South Florida Medical Research and investigator in the Phase 3 BPH study, will also participate in the call.

A live audio webcast will be accessible on the "Investor Relations" page of the Sophiris corporate website at www.SophirisBio.com. A replay will be available at the same location for 60 days.

About Prostate Cancer
Prostate cancer is the second most common form of cancer in men in the US with an estimated 220,800 new cases in 2015. Approximately 80 percent of patients in the US are diagnosed with localized disease. Research has shown that patients with early, localized disease have a low likelihood of the cancer spreading beyond the confines of the prostate; however, many men with clinically significant localized disease do choose to undergo radical treatment. Radical therapies include surgery to remove the entire prostate and/or radiation. Potential toxicities from radical treatments can be significant and permanent and include erectile dysfunction, urinary incontinence, and rectal toxicity.

Topsalysin for the Targeted Treatment of Localized Prostate Cancer
Topsalysin (PRX302) has the potential to provide a focal targeted therapy for the ablation of localized prostate cancer while potentially avoiding many of the complications and side effects associated with whole gland radical treatments. The increasing use of multi-parametric magnetic resonance imaging (mpMRI) and advances in mapping previously obtained mpMRI images with real-time three-dimensional ultrasound images enables physicians to more accurately locate tumors within the prostate when taking biopsies. This increases the accuracy with which men with clinically significant lesions are identified. It also enables the injection of an ablative agent, such as topsalysin, directly into previously identified clinically significant tumors located within the prostate. Topsalysin, an inactivated pore-forming protein, was engineered to be activated only by enzymatically-active PSA, which is present only in prostate tissue. The targeted focal treatment of prostate cancer is in line with current treatments for solid tumors such as breast and liver, where the goal is to remove the tumor and preserve as much of the organ as possible

ArQule Provides Proprietary Pipeline Update for AKT Inhibitors

On January 28, 2016 ArQule, Inc. (NASDAQ:ARQL) reported a pipeline update for its AKT inhibitors, including ARQ 092 and ARQ 751, both orally available, selective pan-AKT inhibitors (Press release, ArQule, JAN 28, 2016, View Source [SID:1234508895]).

ARQ 092 – Lead AKT Inhibitor

The phase 1 trial for ARQ 092 in Proteus syndrome, which was opened for enrollment in November 2015, has completed dosing of its first cohort. The first cohort, consisting of three patients, is being observed for safety. The phase 1 trial is being conducted by our collaborators at the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH). Proteus syndrome is a rare disease that is characterized by overgrowth of the skeleton, skin, adipose tissue and central nervous system. ARQ 092 was recently granted orphan drug designation by the Food and Drug Administration (FDA) in this indication which impacts less than one in a million people worldwide.

Recently, a manuscript was published by the NHGRI of the NIH in Scientific Reports (available on-line at View Source) discussing pre-clinical research with ARQ 092 in Proteus syndrome. This pre-clinical study tested the efficacy of ARQ 092 in suppressing AKT signaling in cells and tissues from patients with Proteus syndrome. Reduced phosphorylation of AKT and downstream targets of AKT in a concentration-dependent manner were observed in as little as two hours without reduction in cell viability.

ArQule continues to enroll patients harboring AKT1 or PI3K mutations in the company sponsored phase 1b expansion cohort of its oncology trial. Cohorts for lymphoma and endometrial are fully enrolled. Thus far the company has observed five partial responses in the phase 1b portion of the trial, three of which occurred in patients whose tumors have AKT1 or PI3K mutations and two of which occurred in patients where the mutational status is unknown.

ARQ 751 – Next Generation AKT Inhibitor

ArQule received FDA approval of its investigational new drug (IND) application for ARQ 751, a next generation AKT inhibitor, in oncology. As published in PLOS ONE, (available on-line at View Source), ARQ 751 has demonstrated signal abrogation and efficacy in pre-clinical in vitro and in vivo models harboring AKT1 and PI3K mutations. The company expects to commence a phase 1 trial in oncology during the first half of 2016 targeting AKT1 and PI3K mutations.

"We are pleased with the two recent publications on our AKT program, and we look forward to further advancing our AKT pipeline in 2016 with ARQ 092 and our next generation AKT inhibitor, ARQ 751," said Brian Schwartz, Chief Medical Officer and Head of Research and Development at ArQule. "The understanding accumulated by us and our collaborators on our AKT program in oncology and rare diseases positions us for leadership in this class. We plan to explore opportunities to advance our trials in oncology as well as in rare over-growth indications beyond Proteus syndrome."

"2015 was an exciting year for ArQule as we were able to bring forward clinical results from our proprietary pipeline which now includes two orphan drug designations from the FDA," said Paolo Pucci, Chief Executive Officer at ArQule. "Looking ahead into 2016, we expect the interim analysis for the tivantinib phase 3 METIV-HCC trial to occur early in the second quarter, and we also expect to be able to make decisions on next steps in clinical development for ARQ 092 in oncology and Proteus syndrome, as well as for ARQ 087 in intrahepatic cholangiocarcinoma (iCCA)."

About Proteus Syndrome

According to the patient advocacy and support group, the Proteus syndrome Foundation (View Source), the condition was named for Proteus, the Greek god who could transform his shape. Patients experience changes in the shapes of certain body structures over time, including abnormal, often asymmetric, massive growth (overgrowth) of the skeleton, skin, adipose tissue and central nervous system out of proportion to the rest of the body, which may appear normal. Although patients may have minimal or no manifestations at birth, the disease develops and becomes apparent in early childhood (6-18 months) and rapidly progresses with intense growth in the first ten years of life. It is primarily a childhood-onset disease but there are very few living affected adults.

Proteus syndrome is a rare condition with an incidence of less than 1 in 1 million people worldwide. Only a few hundred individuals have been reported in the medical literature. At this time, there are more than 120 documented cases worldwide, but because not all cases are documented, it is not known how many individuals have this syndrome. The incidence of Proteus syndrome classifies it as a rare disorder, defined by the National Organization of Rare Diseases (NORD) as any disease affecting fewer than 200,000 Americans.

About the AKT Pathway, ARQ 092 and ARQ 751

ARQ 092 and ARQ 751 are orally bioavailable, selective small molecule inhibitors of the AKT kinases. The AKT pathway when abnormally activated is implicated in multiple oncogenic processes such as cell proliferation and apoptosis. This pathway has emerged as a target of potential therapeutic relevance for compounds that inhibit its activity, which has been linked to a variety of cancers as well as to select non-oncology indications.

ARQ 092, the lead compound in ArQule’s AKT program, has completed phase 1a clinical testing and has advanced into phase 1b expansion testing in cohorts of patients with endometrial cancer, lymphoma and tumors harboring either AKT or PI3K mutations. A number of next-generation compounds in the Company’s AKT program are in early to late stages of pre-clinical development. The company plans to initiate a phase 1 clinical trial in the first half of 2016 for ARQ 751, a next generation AKT inhibitor.

Exelixis Announces U.S. FDA Deems New Drug Application Sufficiently Complete and Grants Priority Review for Cabozantinib as a Treatment for Advanced Renal Cell Carcinoma

On January 28, 2016 Exelixis, Inc. (NASDAQ:EXEL) reported that the U.S. Food & Drug Administration (FDA) has determined the company’s New Drug Application (NDA) for cabozantinib as a treatment for patients with advanced renal cell carcinoma (RCC) who have received one prior therapy to be sufficiently complete to permit a substantive review (Press release, Exelixis, JAN 28, 2016, View Source;p=RssLanding&cat=news&id=2133086 [SID:1234508892]). The NDA will be considered officially filed 60 days from the date of the completion of the submission, or February 20, 2016. The FDA granted Priority Review to the filing and assigned a Prescription Drug User Fee Act action date of June 22, 2016.

"With FDA granting Priority Review to our application, Exelixis is one step closer to offering physicians cabozantinib as an important new therapeutic option for their patients with advanced renal cell carcinoma," said Michael M. Morrissey, Ph.D., president and CEO of Exelixis. "While we work closely with the FDA during the review process, Exelixis will continue to execute on our commercial plans, including our commitment to be ready for a potential launch by April 1st of this year."

A Priority Review designation is granted by the FDA for drugs that, if approved, would be significant improvements in the treatment, prevention or diagnosis of a disease. Previously, the FDA granted cabozantinib Breakthrough Therapy designation (August 2015) and Fast Track designation (April 2015) for the compound’s proposed RCC indication.

The NDA 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 demonstrating that the trial had met its primary endpoint of improving progression-free survival; compared with everolimus, 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.

On January 11, 2016, Exelixis announced the submission of a Marketing Authorization Application (MAA) for cabozantinib as a treatment for patients with advanced RCC who have received one prior therapy to the European Medicines Agency (EMA). The EMA’s Committee for Medicinal Products for Human Use (CHMP) previously granted accelerated assessment to cabozantinib for advanced RCC. As a result, the company’s MAA will be eligible for a 150-day review, versus the standard 210 days (excluding clock stops when information is requested by CHMP).

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 NDA 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 who have received prior VEGF receptor TKIs. 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 (VHL) protein function, either due to gene inactivation or epigenetic silencing, resulting in a stabilization of the hypoxia-inducible transcription factors (HIFs) 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.