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Phase 3 Study Demonstrates Aranesp® (Darbepoetin Alfa) Reduces Red Blood Cell Transfusions In Patients With Myelodysplastic Syndrome (MDS)

On February 15, 2016 Amgen (NASDAQ:AMGN) reported that the randomized, double-blind, placebo-controlled Phase 3 Aranesp (darbepoetin alfa) ARCADE trial met its primary endpoint of reducing the incidence of red blood cell transfusions in anemic patients with low and intermediate-1 risk MDS at the end of the blinded 25-week study period(Press release, Amgen, FEB 15, 2016, View Source [SID:1234509057]). Aranesp also significantly improved erythroid response, a key measure of the formation of new red blood cells. Detailed results will be submitted to a future medical conference and for publication.

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Safety data was consistent with the known safety profile of Aranesp, and the adverse events were generally balanced between treatment arms. The adverse events reported in the Aranesp arm at least five percent more frequently than in the placebo group were fatigue, pyrexia, headache and myalgia.

MDS is among the most common type of bone marrow failure syndromes in adults.1 The disease occurs when immature blood cells do not mature in the bone marrow. Patients with MDS have fewer healthy white blood cells, red blood cells and platelets, and are at risk of infection, anemia or bleeding.2 Current treatments for MDS include blood transfusions, chemotherapy and stem cell transplants.

"We are pleased to see positive results from this study, as anemia treatment options for myelodysplastic syndrome are limited and can place a significant burden on patients," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen.

About the ARCADE Study
The Phase 3 ARCADE trial was a multicenter, randomized, double-blind, placebo-controlled study evaluating Aranesp in 146 patients with low or intermediate-1 risk MDS who had not previously taken ESAs or biologic response modifiers. During a 24-week period, patients received either Aranesp 500 μg (n=97) or placebo (n=49) every three weeks. At week 25, when the primary and key secondary endpoints were assessed, patients underwent an end-of-treatment period (EOTP) visit and could subsequently enter a 48-week active treatment period where all participants crossed over to receive Aranesp, with dose escalation allowed beginning on week 31. Treatment continued until week 72 or 73, and long-term follow up continues to occur every 26 weeks, for a minimum of three years.

About MDS
MDS affects more than 30,000 people in the United States annually.1 People undergoing certain types of chemotherapy or radiation treatment for cancer may be at increased risk of developing treatment-related MDS.3 Patients with MDS affecting red blood cells often experience anemia.4

About Aranesp (darbepoetin alfa) in the U.S.
Aranesp is indicated for the treatment of anemia due to chronic kidney disease (CKD), including patients on dialysis and patients not on dialysis.

Aranesp is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.

Limitations of Use:
Aranesp has not been shown to improve quality of life, fatigue, or patient well-being.
Aranesp is not indicated for use:

In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
As a substitute for red blood cell transfusions in patients who require immediate correction of anemia.
Important U.S. Safety Information for Aranesp
WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE

Chronic Kidney Disease:

In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL.
No trial has identified a hemoglobin target level, Aranesp dose, or dosing strategy that does not increase these risks.
Use the lowest Aranesp dose sufficient to reduce the need for red blood cell (RBC) transfusions.
Cancer:

ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers.
Because of these risks, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/or dispense Aranesp to patients with cancer. To enroll in the ESA APPRISE Oncology Program, visit www.esa-apprise.com or call 1-866-284-8089 for further assistance.
To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions.
Use ESAs only for anemia from myelosuppressive chemotherapy.
ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
Discontinue following the completion of a chemotherapy course.
Aranesp is contraindicated in patients with uncontrolled hypertension, pure red cell aplasia (PRCA) that begins after treatment with Aranesp or other erythropoietin protein drugs, or serious allergic reactions to Aranesp.

Use caution in patients with CKD and coexistent cardiovascular disease and stroke. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of > 1 g/dL over 2 weeks may contribute to these risks. In controlled clinical trials of patients with cancer, Aranesp and other ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures. Control hypertension prior to initiating and during treatment with Aranesp.

Aranesp increases the risk of seizures in patients with CKD. Monitor patients closely for new-onset seizures, premonitory symptoms, or change in seizure frequency.

For lack or loss of hemoglobin response to Aranesp, initiate a search for causative factors. If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA. Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with Aranesp. This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which Aranesp is not approved). If severe anemia and low reticulocyte count develop during treatment with Aranesp, withhold Aranesp and evaluate patients for neutralizing antibodies to erythropoietin. Permanently discontinue Aranesp in patients who develop PRCA following treatment with Aranesp or other erythropoietin protein drugs. Do not switch patients to other ESAs.

Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with Aranesp. Immediately and permanently discontinue Aranesp if a serious allergic reaction occurs.

Adverse reactions (≥ 10%) in Aranesp clinical studies in patients with CKD were hypertension, dyspnea, peripheral edema, cough, and procedural hypotension. Adverse reactions (≥ 1%) in Aranesp clinical studies in cancer patients receiving chemotherapy were abdominal pain, edema, and thrombovascular events.

To see the Aranesp Prescribing Information, including Boxed Warnings, and Medication Guide visit www.aranesp.com.

OPKO Health Acquires Interest in Xenetic

On February 12, 2016 Xenetic Biosciences, Inc. (OTCQB: XBIO), a biopharmaceutical company focused on developing next-generation biologic drugs and novel oncology therapeutics ("Xenetic") reported that OPKO Health, Inc. (NYSE: OPK) has acquired an approximate 6.3% interest in Xenetic (Press release, Xenetic Biosciences, FEB 12, 2016, View Source [SID1234537813]).

Commenting on the investment in Xenetic, Dr. Phillip Frost, CEO and Chairman of OPKO Health, Inc., stated, "Xenetic has many novel technologies that address unmet needs in various orphan cancer indications, and we believe the science and the clinical strategy have the promise to create significant shareholder value."

Scott Maguire, President and Chief Executive Officer of Xenetic commented, "We are proud to have OPKO Health as one of our largest shareholders joining our other strategic shareholders, Baxalta and Serum Institute of India. Dr. Frost has an outstanding track record in creating shareholder value in our industry."

UK Court Rules Against Lilly in Alimta Vitamin Regimen Patent Lawsuit

On February 12, 2016 Eli Lilly and Company (NYSE: LLY) reported that the UK High Court decided the Alimta (pemetrexed disodium) vitamin regimen patent would not presently be infringed by Actavis marketing pemetrexed trometamol in the UK, France, Italy and Spain with instructions to dilute the product only with dextrose solution (Press release, Eli Lilly, FEB 12, 2016, View Source [SID:1234509078]).

In June of 2015, the UK Court of Appeal held that Lilly’s patent would be indirectly infringed by Actavis marketing certain alternative salt forms of pemetrexed with instructions to dilute the product with saline solution. However, the Court of Appeal left open the question of whether an alternative salt form with instructions to dilute only in dextrose solution would infringe.

The court based its decision of non-infringement on Actavis complying with its stated intentions as to how it will market its product and certain circumstances not changing over the remaining life of the patent. In its decision, the UK court accepts that it is not able to predict what will happen in the future and expressly allows either party to ask for the decision to be revisited if there is a material change of circumstances at any point in the remaining life of the patent, which expires in June 2021.

Lilly plans to seek permission to appeal today’s decision to the UK Court of Appeal.

In major European countries, the compound patents for Alimta expired in December 2015. The Alimta vitamin regimen patents expire in June 2021.

"We strongly disagree with the ruling by the UK High Court granting a declaration of non-infringement on the Alimta vitamin regimen patents under these circumstances. We plan to seek permission to appeal this ruling," said Michael J. Harrington, senior vice president and general counsel for Lilly.

In addition, Lilly has applied for permission to appeal the direct infringement aspect of the June 2015 Court of Appeal decision to the UK Supreme Court. That request is pending.

In a separate proceeding in the first quarter of 2015, the Dusseldorf Court of Appeal ruled the Alimta vitamin regimen patent would not be infringed by a generic competitor that has stated intent to market pemetrexed dipotassium in Germany after the compound patent expiration in December 2015. Lilly has recently been granted permission to appeal this ruling to the Federal Supreme Court of Germany, which is scheduled to be heard mid-2016. Lilly has also recently received a preliminary injunction against a different generic competitor to restrict marketing of a copycat pemetrexed product.

In the fourth quarter of 2015, a generic competitor unilaterally withdrew its appeal in the case regarding the validity of the Alimta vitamin regimen patent before the Technical Board of Appeal of the European Patent Office (EPO). In view of the withdrawal of the appeal, the decision of the Opposition Division of the EPO finding the patents valid is final, and there cannot be further validity challenges to the vitamin regimen patents for Alimta centrally before the EPO.

Clovis Oncology Announces Rociletinib New Drug Application Scheduled for Presentation at Upcoming FDA Oncologic Drugs Advisory Committee Meeting

On February 12, 2016 Clovis Oncology, Inc. (NASDAQ: CLVS) reported that the U.S. Food and Drug Administration (FDA) has scheduled the New Drug Application (NDA) for rociletinib for discussion by the Oncologic Drugs Advisory Committee (ODAC) on April 12, 2016 (Press release, Clovis Oncology, FEB 12, 2016, View Source [SID:1234509053]).

Rociletinib is an investigational therapy for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) who have been previously treated with an EGFR-targeted therapy and have the EGFR T790M mutation.

The ODAC reviews and evaluates data concerning the safety and effectiveness of marketed and investigational human drug products for use in the treatment of cancer and makes recommendations to the FDA.

"We are actively preparing for this advisory committee meeting and look forward to the discussion about rociletinib," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "New treatments are needed for this hard-to-treat patient population, and we believe that rociletinib represents an important new option for patients with mutant EGFR T790M-positive lung cancer."

About Rociletinib

Rociletinib is the company’s novel, oral, targeted covalent (irreversible) mutant-selective inhibitor of EGFR in development for the treatment of NSCLC in patients with initial activating EGFR mutations, as well as the dominant resistance mutation T790M. Data from both the pivotal, single-arm TIGER-X and TIGER-2 clinical trials served as the basis for the U.S. and EU regulatory submissions for the treatment of advanced mutant EGFR T790M-positive lung cancer. Rociletinib was granted Breakthrough Therapy designation by the FDA in May 2014.

Celsion Corporation Highlights Recent Pipeline Developments for its GEN-1 Immunotherapy Program and Provides Business Update

On February 12, 2016 Celsion Corporation (Celsion) (NASDAQ: CLSN), a fully-integrated oncology company focused on the development of a portfolio of innovative cancer treatments, reported recent accomplishments related to the Company’s GEN-1 immunotherapy pipeline and provided a general business update (Press release, Celsion, FEB 12, 2016, View Source [SID:1234509051]). Celsion also announced the completion of enrollment of the first cohort of patients in its Phase 1b dose escalating clinical trial (the OVATION Study) combining GEN-1, the Company’s DNA-based immunotherapy, with the standard of care for the treatment of newly-diagnosed ovarian cancer patients who will undergo neoadjuvant chemotherapy followed by surgical resection of their tumor.

"GEN-1 is designed to locally activate IL-12 production using our novel targeted non-viral delivery platform for a sustained period for up to 7 days in the tumor environment," stated Dr. Nicolas Borys, Celsion’s senior vice president and chief medical officer. "Emerging preclinical and translational data demonstrate that GEN-1 stimulates the local cellular production and secretion of highly-tolerable endogenous IL-12, a potent multi-mechanistic anti-cancer agent, while limiting toxicities, poor tolerability, and poor pharmacokinetics associated with systemically administered recombinant IL-12."

The OVATION Study

The first two patients in the OVATION Study who completed treatment have shown promising results. Both patients reported stable disease with a dramatic drop in their CA-125 protein levels of 89% and 98%. Cancer antigen 125 (CA-125) is used to monitor certain cancers during and after treatment. CA-125 is present in greater concentrations in ovarian cancer cells than in other cells. A 50% reduction in CA-125 levels is considered meaningful. Both patients’ CA-125 levels were below the normal healthy level of 35 U/mL. In addition, both patients experienced successful surgical resections of their tumors with one patient reporting a R0 resection which indicates a microscopically margin-negative resection in which no gross or microscopic tumor remains in the tumor bed.

The OVATION Study will continue into 2016 at higher doses of GEN-1 with the goal to identify a safe, tolerable and therapeutically active dose of GEN-1 by recruiting and maximizing an immune response. Celsion has initiated four clinical sites at the University of Alabama at Birmingham; Oklahoma University Medical Center; Washington University in St. Louis and the Medical College of Wisconsin. The trial is designed to enroll three to six patients per dose cohort and will evaluate safety and efficacy and attempt to define an optimal dose for a follow-on Phase I/II study combining GEN-1 with Avastin and Doxil.

GEN-1 + Avastin + Doxil Program

The Company has completed various preclinical studies combining GEN-1 with Avastin and Doxil, the current standard of care for the treatment of platinum resistant ovarian cancer, which has demonstrated synergistic anti-cancer effects. The Company’s preclinical data abstract summarizing these studies has been accepted for presentation at the upcoming AACR (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans. Data from these studies will be used to support an IND filing for a Phase I/II clinical trial evaluating the combination in recurrent ovarian cancer later this year.

Supporting Translational Data

In January 2016, the Company reported translational research data from its recently completed Phase 1b Study of GEN-1 in combination with PEGylated doxorubicin (Doxil) in patients with platinum-resistant ovarian cancer. This important data provides evidence that intraperitoneally-administered GEN-1 produces an immunologically distinct IL-12 protein that is localized at the tumor site and lasts for up to one week after a single treatment. Furthermore, concomitant increases in IFN-γ and TNF- α indicate that the IL-12 produced following treatment with GEN-1 treatment is immunologically active.

In addition to this strongly supportive translational data, GEN-1 has demonstrated encouraging safety and efficacy data in this Phase 1b trial in combination with Doxil as summarized below:

Findings from this trial demonstrated an overall clinical benefit of 57.1% for all treatment arms, with a partial response (PR) rate of 21.4% and a stable disease (SD) rate of 35.7%
There was a 100% overall clinical benefit observed at the highest dose cohort in this difficult-to-treat patient population (PR=33% and SD=67%) in all six evaluable patients
GEN-1 was well tolerated, with no dose limiting toxicities and no overlapping toxicities between GEN-1 and Doxil.
Business Update

The Company also reported a year-end cash position of $20.1 million (unaudited) compared to $24.1 million reported at the end of the third quarter of 2015.

"Celsion continues to make significant progress across our pipeline of directed chemotherapies, immunotherapies and RNA-based therapies, which we anticipate will position the company to achieve value-creating milestones in 2016," said Michael H. Tardugno, chairman, president and CEO. "As we look toward 2016, we will continue to maintain tight controls over our spending with a sharp focus on those programs that will drive both near-term and long-term value for our shareholders."

About GEN-1 Immunotherapy

GEN-1, designed using the TheraPlas platform technology, is an IL-12 DNA plasmid vector encased in a nanoparticle delivery system which enables cell transfection followed by persistent, local secretion of the IL-12 protein. IL-12 is one of the most active cytokines for the induction of potent anti-cancer immunity acting through the induction of T-lymphocyte and natural killer (NK) cell proliferation. The Company has previously reported positive safety and encouraging Phase I results with GEN-1 given as monotherapy in patients with peritoneally metastasized ovarian cancer and in combination with PEGylated doxorubicin in patients with platinum resistant ovarian cancer.