Effects of Src-kinase inhibition in cancer-induced bone pain.

Bone metastases occur frequently in advanced breast, lung, and prostate cancer, with approximately 70% of patients affected. Pain is a major symptom of bone metastases, and current treatments may be inadequate or have unacceptable side effects. The mechanisms that drive cancer-induced bone pain are not fully understood; however, it is known that there is sensitization of both peripheral bone afferents and central spinal circuits. It is well established that the N-methyl-D-aspartate receptor plays a major role in the pathophysiology of pain hypersensitivity. Inhibition of the non-receptor tyrosine kinase Src controls N-methyl-D-aspartate receptor activity and inhibiting Src reduces the hypersensitivity associated with neuropathic and inflammatory pains. As Src is also implicated in osteoclastic bone resorption, we have investigated if inhibiting Src ameliorates cancer-induced bone pain. We have tested this hypothesis using an orally bioavailable Src inhibitor (saracatinib) in a rat model of cancer-induced bone pain.
Intra-tibial injection of rat mammary cancer cells (Mammary rat metastasis tumor cells -1), but not vehicle, in rats produced hindpaw hypersensitivity to thermal and mechanical stimuli that was maximal after six days and persisted for at least 13 days postinjection. Daily oral gavage with saracatinib (20 mg/kg) beginning seven days after intra-tibial injection reversed the thermal hyperalgesia but not the mechanical allodynia. The analgesic mechanisms of saracatinib appear to be due to an effect on the nervous system as immunoblotting of L2-5 spinal segments showed that mammary rat metastasis tumor cells-1 injection induced phosphorylation of the GluN1 subunit of the N-methyl-D-aspartate receptor, indicative of receptor activation, and this was reduced by saracatinib. Additionally, histology showed no anti-tumor effect of saracatinib at any dose and no significant effect on bone preservation.
This is the first demonstration that Src plays a role in the development of cancer-induced bone pain and that Src inhibition represents a possible new analgesic strategy for patients with bone metastases.
© The Author(s) 2016.

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Biogen Reports First Quarter 2016 Revenues of $2.7 Billion

On April 21, 2016 Biogen Inc. (NASDAQ: BIIB reported first quarter 2016 financial results, including:

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Total revenues of $2.7 billion, a 7% increase versus the same period in the prior year (Press release, Biogen, APR 21, 2016, View Source [SID:1234511220]). Growth was driven by a 15% increase in worldwide TECFIDERA revenues as well as increased revenues from ELOCTATE and ALPROLIX. Revenues were partially offset by a decrease in worldwide interferon sales.

Foreign exchange, including a $26 million reduction in hedging gains, negatively impacted total revenues by approximately $50 million compared to the first quarter of 2015.

Non-GAAP diluted earnings per share (EPS) of $4.79, a 25% increase versus the same period in the prior year. Growth was driven by a combination of increased revenues, lower SG&A and R&D expense, and a lower share count.
Non-GAAP net income attributable to Biogen Inc. increased 17% to $1.0 billion.
GAAP diluted EPS of $4.43, a 27% increase versus the same period in the prior year.
GAAP net income attributable to Biogen Inc. increased 18% to $971 million.
(In millions, except per share amounts) Q1 ‘16 Q4 ‘15 Q1 ‘15 Q1 ‘16 v. Q4 ‘15 Q1 ‘16 v. Q1 ‘15
Total revenues $ 2,727 $ 2,839 $ 2,555 (4%) 7%
Non-GAAP net income* $ 1,049 $ 995 $ 900 5% 17%
Non-GAAP EPS $ 4.79 $ 4.50 $ 3.82 6% 25%

GAAP net income* $ 971 $ 832 $ 823 17% 18%
GAAP EPS $ 4.43 $ 3.77 $ 3.49 18% 27%
*Net income attributable to Biogen Inc.
A reconciliation of GAAP to Non-GAAP quarterly financial results can be found in Table 3 at the end of this release.

"Our leading multiple sclerosis portfolio, a growing hemophilia business, and our ongoing focus on managing expenses led to robust earnings growth in the first quarter," said Chief Executive Officer George A. Scangos, Ph.D. "We are pleased with the recent European approval of BENEPALI and positive CHMP opinion for FLIXABI, both anti-TNF biosimilars. We are also encouraged by the recent positive CHMP opinion of ALPROLIX for hemophilia B in Europe."

"The remainder of 2016 will be an exciting period as we look to advance a number of potential breakthrough therapies in the clinic," Dr. Scangos continued. "We are executing Phase 3 clinical trials for aducanumab in early Alzheimer’s disease and, along with our collaboration partner Ionis, we are progressing nusinersen in spinal muscular atrophy. In the coming months, we expect opicinumab (anti-LINGO) Phase 2 data to provide us with a better understanding of its potential as a reparative therapy for multiple sclerosis."

Revenue Highlights

(In millions) Q1 ‘16 Q4 ‘15 Q1 ‘15 Q1 ‘16 v. Q4 ‘15 Q1 ‘16 v. Q1 ‘15
Multiple Sclerosis (MS):
TECFIDERA $ 946 $ 993 $ 825 (5%) 15%
Total Interferon $ 670 $ 740 $ 755 (9%) (11%)
AVONEX $ 564 $ 637 $ 693 (11%) (19%)
PLEGRIDY $ 106 $ 103 $ 62 4% 72%
TYSABRI $ 477 $ 481 $ 463 (1%) 3%
FAMPYRA $ 20 $ 28 $ 20 (27%) 1%

Hemophilia:
ALPROLIX $ 75 $ 71 $ 43 5% 74%
ELOCTATE $ 108 $ 101 $ 54 6% 101%

Other Product Revenues:
FUMADERM $ 11 $ 13 $ 14 (10%) (16%)
BENEPALI $ 2 $ - $ - N/A N/A

Total Product Revenues: $ 2,309 $ 2,426 $ 2,172 (5%) 6%

Anti-CD20 Revenues $329 $334 $331 (1%) (0%)
Other Revenues $88 $80 $52 11% 69%

Total Revenues $2,727 $2,839 $2,555 (4%) 7%
Note: Numbers may not foot due to rounding
Expense Highlights

R&D expense was $437 million compared to $542 million in the fourth quarter of 2015 and $461 million in the first quarter of 2015.
R&D expense decreased 19% versus the fourth quarter of 2015, reflecting a $60 million payment made to Mitsubishi Tanabe Pharma Corporation in the fourth quarter of 2015 along with the timing of clinical manufacturing runs and other R&D activities.
SG&A expense was $497 million compared to $583 million in the fourth quarter of 2015 and $560 million in the first quarter of 2015. The company remains focused on achieving additional savings in non-labor expenses, with the objective of reducing lower priority fees and services expenses.
Other Financial Highlights

For the first quarter of 2016, the Company’s weighted average diluted shares were 219 million.
At the end of the first quarter of 2016, Biogen had cash, cash equivalents and marketable securities totaling approximately $6.8 billion, and $6.5 billion in notes payable and other financing arrangements.
Recent Events

This week, Biogen is presenting new data supporting the Company’s marketed and pipeline MS therapies at the 68th American Academy of Neurology (AAN) Annual Meeting. Presentations include efficacy data for TECFIDERA in newly diagnosed patients; data highlighting efficacy on key cognitive outcomes and the reversibility of the targeted mechanism of action of ZINBRYTATM; 10 year real-world evidence of the proven long-term efficacy of TYSABRI in patients with high disease activity; and analyses showing that PLEGRIDY reduces conversion of MRI lesions to T1 black holes.

At this week’s AAN Meeting, Biogen’s collaboration partner Ionis Pharmaceuticals also presented an update from its ongoing open-label Phase 2 study of nusinersen in infants with spinal muscular atrophy.

In April 2016, Samsung Bioepis, the joint venture between Biogen and Samsung BioLogics, received a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommending that marketing authorisation be granted for FLIXABI, an infliximab biosimilar candidate referencing Remicade. If approved, FLIXABI will be the second anti-TNF biosimilar manufactured and commercialized by Biogen in the European Union (EU).

In March 2016, Biogen announced the appointment of Michel Vounatsos as Executive Vice President and Chief Commercial Officer effective April 18, 2016. Mr. Vounatsos joins Biogen following a distinguished 20 year career at Merck.

In February 2016, Swedish Orphan Biovitrum AB (publ) (Sobi) and Biogen received a positive opinion from the CHMP recommending that marketing authorisation be granted for ALPROLIX, a recombinant factor IX Fc fusion protein therapy for the treatment of hemophilia B.

In February 2016, the Roche Group announced that the US Food and Drug Administration approved Gazyva plus bendamustine chemotherapy followed by Gazyva alone as a new treatment for people with follicular lymphoma who did not respond to a Rituxan-containing regimen, or had their follicular lymphoma return after such treatment. Follicular lymphoma is the most common type of indolent (slow-growing) non-Hodgkin lymphoma (NHL) and accounts for approximately one in five cases of NHL. In the U.S., Biogen shares operating profits and losses relating to GAZYVA with Genentech, a Roche Group company.

In February 2016, Biogen announced that it joined the Centre for Therapeutic Target Validation (CTTV), the pioneering public-private collaboration to improve the success rate for discovering new medicines. The CTTV fosters deep, ongoing interactions between academic and industry members for the purpose of developing open, transformative approaches to selecting and validating novel targets in drug development.

In January 2016, following approval from the European Commission, Biogen launched BENEPALI, the first etanercept biosimilar referencing Enbrel to be approved in the EU. BENEPALI is now available in the UK, Germany, Denmark, Norway, Sweden, and the Netherlands.

Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment.

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy.
Copyright © 2016 Elsevier Inc. All rights reserved.

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TapImmune Announces Phase 2 Ovarian Cancer Trial Study with AstraZeneca/MedImmune and Sloan Kettering Cancer Institute

On April 21, 2016 TapImmune,Inc. (TPIV), a clinical-stage immunology-oncology company specializing in the development of innovative peptide and gene-based immunotherapeutics and vaccines for the treatment of cancer & metastatic disease, reported plans to initiate a Phase 2 trial of its cancer vaccine, TPIV 200, a multi-epitope anti-folate receptor vaccine (FRalfa), in combination with Astra Zeneca (NYSE: AZN) durvalumab (MEDI4736), an anti-PD-L1 antibody, in patients with platinum-resistant ovarian cancer (Press release, TapImmune, APR 21, 2016, View Source [SID:1234512243]). The study will commence in the second quarter of 2016 at Memorial Sloan Kettering Cancer Center in New York and will be led by Jason Konner, M.D. as Principal Investigator.

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The two Companies will share clinical costs, while TapImmune will supply TPIV 200 and MedImmune will supply Durvalumab (MED14736) for the trials. TapImmune recently obtained Orphan Drug Designation for TPIV 200 in ovarian cancer from the U.S. Food and Drug Administration.

This single arm Phase 2 trial will include 40 women with high-grade ovarian, tubal, or primary peritoneal carcinomas, who have progressed within 6 months of their most recent platinum chemotherapy. The primary objective of the study is to determine the effectiveness of the combination by measuring Overall Response Rate [ORR = Complete Response (CR) + Partial Response (PR)] by RECIST and Progression Free Survival (PFS) rate at 6 months. Secondary endpoints will be safety and immune and correlation of FRalfa-specific immune responses with clinical efficacy.

"This collaboration is a significant event for TapImmune," stated Dr. Glynn Wilson, Chairman and CEO of TapImmune. "We are delighted to bring a leading T-cell vaccine platform into this combination study and to work with AstraZeneca/Medimmune and Sloan Kettering in a patient population that is in dire need of an effective treatment."

"This study is part of a larger Phase 2 strategy for TPIV 200 that is designed to greatly increase our understanding of the vaccine while providing clinical evidence of efficacy," Dr. Wilson added.

TPIV 200 is a multi-epitope peptide vaccine that targets Folate Receptor Alpha, which is overexpressed in multiple cancers including over 90% of ovarian cancer cells. In Phase I clinical studies conducted at the Mayo Clinic in patients with breast and ovarian cancer, this vaccine was shown to be safe and well tolerated and to give robust cellular immune responses in 20 out of 21 evaluable patients.

About Durvalumab (MEDI4736)

Durvalumab is an investigational human monoclonal antibody directed against PD-L1 developed at MedImmune LLC. Signals from PD-L1 help tumors avoid detection by the immune system. Durvalumab blocks these signals, countering the tumor’s immune-evading tactics. Durvalumab is being developed, alongside other immunotherapies, to empower the patient’s immune system and attack the cancer. Durvalumab is being investigated in an extensive clinical trial program, as monotherapy or in combination with tremelimumab, in NSCLC, head and neck, gastric, pancreatic, bladder and blood cancers.

Pharmacokinetic properties of nintedanib in healthy volunteers and patients with advanced cancer.

Nintedanib, a triple angiokinase inhibitor, has undergone clinical investigation for the treatment of solid tumors and idiopathic pulmonary fibrosis. Nintedanib (Vargatef() ) plus docetaxel is approved in the EU for the treatment of patients with adenocarcinoma NSCLC after first-line chemotherapy, and as monotherapy (Ofev() ) in the USA and EU for the treatment of patients with idiopathic pulmonary fibrosis. Pharmacokinetics (PK) of nintedanib after oral single- and multiple-doses and intravenous (i.v.) administration were assessed using three datasets: (1) an absolute bioavailability trial that enrolled 30 healthy volunteers; (2) a pooled data analysis of four studies that enrolled a total of 113 healthy volunteers; (3) a pooled data analysis of four studies that enrolled a total of 149 patients with advanced cancer. In the absolute bioavailability trial of healthy volunteers, nintedanib showed a high total clearance (geometric mean: 1390 mL/min) and a high volume of distribution at steady state (Vss = 1050 L). Urinary excretion of i.v. nintedanib was about 1% of dose; renal clearance was about 20 mL/min and therefore negligible. There was no deviation from dose proportionality after i.v. administration in the dose range tested. Absolute bioavailability of oral nintedanib (100 mg capsule) relative to i.v. dosing (4-hour infusion, 6 mg) was slightly below 5%. Nintedanib was quickly absorbed after oral administration. It underwent rapid and extensive first-pass metabolism and followed at least biphasic disposition kinetics. In advanced cancer patients, steady state was reached at the latest at 7 days for twice-daily dosing. Nintedanib’s PK was time-independent; accumulation after repeated administration was negligible. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.

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