Synthesis and Antiproliferative and Metabolic Evaluations of Novel Securinine Derivatives.

New securinine analogues have been prepared by semisynthesis. Two series were developed using either Suzuki or Sonogashira cross coupling reactions. The in vitro cytotoxicity of the compounds was assayed against HCT-116 colon cancer cells. The most potent derivatives showed promising growth inhibition on four tumoral cell lines giving a valuable insight on the structure-activity relationship (SAR) of securinine. Moreover, high antiproliferative effect against A-375 (melanoma) was observed with IC50 up to 60 nM.

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Immune Therapeutics Signs Binding Letter of Intent to Acquire Chinese CAR-T Technology and Clinical Data

On Apr 21, 2016 Immune Therapeutics Inc. (OTCQB: IMUN) reported that they have signed a binding Letter of Intent to acquire Chinese Chimeric Super Antigen Receptor T cell (CAR-T) cocktail therapy, Immuno-Oncology patents (pending), manufacturing technology, and clinical data of the aforementioned therapies from Super-T Cell Cancer Company ("STCC") a newly formed corporation (Press release, Immune Therapeutics, APR 21, 2016, View Source [SID:1234514893]).

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"This CAR-T cell technology licensing further accelerates IMUN’s growth in the Immuno-Oncology field as we evaluate paths to commercialization both in China and other Emerging Markets," commented Christopher Pearce, Chief Operating Officer.
CAR-T cell therapy involves engineering cancer patients’ own immune cells to recognize and attack cancer tumors. CAR-T therapy has great potential to improve patient-specific cancer therapy in a profound way. N umerous studies have implicated regulatory T cells as key mediators in the creation of an immunosuppressed microenvironment that enables tumors to escape attack by the host immune system. The Super CAR-T Cocktail therapy has shown promise in early human clinical trials for the treatment of blood cancer, renal, cervical and hepatic cancer.

"We are very impressed by the quality of the work done by Professor Shan and his team, and are excited by the safe and efficacious profile of this novel CAR-T cocktail therapy for cancerous diseases. This is the beginning of a long-term strategic partnership between IMUN and STCC. Together, we will expeditiously continue our quest in developing more affordable, safer, and more effective cancer immunotherapy programs," said Noreen Griffin, Chief Executive Officer of Immune Therapeutics, Inc.
The need in China for new affordable therapies is critical. It is predicted that there will be about 4,292,000 newly diagnosed invasive cancer cases in 2016, corresponding to almost 12,000 new cancer diagnoses on average each day. IMUN believes that once approved it could capture 5% of the market in the first year.

Discovery and Optimization of Macrocyclic Quinoxaline-pyrrolo-dihydropiperidinones as Potent Pim-1/2 Kinase Inhibitors.

The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization and developed a series of 13-membered macrocycles. The structure-activity relationships of the macrocyclic linker were systematically explored, leading to the identification of 9c as a potent, subnanomolar inhibitor of Pim-1 and -2. This molecule also potently inhibited Pim kinase activity in KMS-12-BM, a multiple myeloma cell line with relatively high endogenous levels of Pim-1/2, both in vitro (pBAD IC50 = 25 nM) and in vivo (pBAD EC50 = 30 nM, unbound), and a 100 mg/kg daily dose was found to completely arrest the growth of KMS-12-BM xenografts in mice.

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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.